Brain Research 1821 (2023) 148589

Contents lists available at ScienceDirect

Brain Research
journal homepage: www.elsevier.com/locate/brainres

Alzheimer’s disease: The role of T lymphocytes in neuroinflammation

and neurodegeneration
Moses O. Asamu a, c, 1, Oladapo O. Oladipo b, c, *, 1, Oluseun A. Abayomi c, d, Afeez A. Adebayo b, c
a
Department of Anatomy, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
b
Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
c
College of Health Sciences, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
d
Olabisi Onabanjo University Teaching Hospital (OOUTH), Sagamu, Ogun State, Nigeria

A R T I C L E I N F O A B S T R A C T

Keywords: Alzheimer’s disease, the leading cause of progressive cognitive decline globally, has been reported to be
Alzheimer’s disease enhanced by neuroinflammation. Brain-resident innate immune cells and adaptive immune cells work together
Microglia to produce neuroinflammation. Studies over the past decade have established the neuroimmune axis present in
T lymphocyte
Alzheimer’s disease; the crosstalk between adaptive and innate immune cells within and outside the brain is
Neuroinflammation
Neurodegeneration
crucial to the onset and progression of Alzheimer’s disease. Although the role of the adaptive immune system in
Alzheimer’s disease is not fully understood, it has been hypothesized that the brain’s immune homeostasis is
significantly disrupted, which greatly contributes to neuroinflammation. Brain-infiltrating T cells possess
proinflammatory phenotypes and activities that directly contribute to neuroinflammation. The pro-inflammatory
activities of the adaptive immune system in Alzheimer’s disease are characterized by the upregulation of effector
T cell activities and the downregulation of regulatory T cell activities in the brain, blood, and cerebrospinal fluid.
In this review, we discuss the major impact of T lymphocytes on the pathogenesis and progression of Alzheimer’s
disease. Understanding the role and mechanism of action of T cells in Alzheimer’s disease would significantly
contribute to the identification of novel biomarkers for diagnosing and monitoring the progression of the disease.
This knowledge could also be crucial to the development of immunotherapies for Alzheimer’s disease.

1. Introduction
Alzheimer’s disease (AD) is a multifactorial, neurodegenerative
condition characterized by progressive memory loss and impairment in
cognition (Reddy et al., 2018). Reports of the incidence and mortality of
AD in the USA presented it as the seventh leading cause of death, with an
incidence of about 6.5 million and a projected 13.8 million by 2060
([xxxx, 0000]). Likewise, the 2016 World Alzheimer’s Report projected
that from 2016 to 2050, there would be an increase from 46.8 million to
131 million in the incidence of AD across the globe (Albrecht et al.,
2021). Despite several scientific studies on AD’s pathogenesis, etiology,
progression, and features, there is no established cure. Thus, AD is a
global concern that significantly threatens human life expectancy.
AD results in brain alterations that cumulatively manifest in its
development and clinical presentation (Alonso Adel et al., 2004). Ag­
gregation and buildup of intracellular neurofibrillary tangles (NFT, also
tau tangles) and abnormal extracellular clumps (amyloid plaques) have
been reported to be the main defining structural changes occurring in

Abbreviations: AD, Alzheimer’s disease; NFT, neurofibrillary tangles; Aβ, beta-amyloid; PS-1 and PS-2, presenilins; APP, amyloid precursor protein; BBB, blood-
brain barrier; ApoE, apolipoprotein E; BACE1, beta-site AβPP-cleaving enzyme; CSF, cerebrospinal fluid; ZO1, zonaoccludens protein 1; MCI, mild cognitive decline;
CAA, Cerebral amyloid angiopathy; CNS, central nervous system; Treg, regulatory T cell; Teff, effector T cells; Th-1, helper T cell-1; Th-17, helper T cell-17; RORγt,
retinoic acid receptor-related orphan nuclear receptor γt; MHC, major histocompatibility complex; EAE, experimental autoimmune encephalomyelitis; CTLA-4,
cytotoxic T-lymphocyte-associated protein-4; PD-1, programmed cell death-1; CCR2, C-C motif chemokine receptor 2; CCR5, C-C chemokine receptor type 5; CXCR2,
C-X-C chemokine receptor 2; ICAM-1, intercellular adhesion molecule 1; VCAM-1, Vascular cell adhesion molecule 1; M1, pro-inflammatory microglia; M2, anti-
inflammatory microglia; MIP-1 α, macrophage inflammatory proteins-1α; CX3CR1, CX3C motif chemokine receptor 1; RAGE, receptor for advanced glycation end
products.
* Corresponding author.
E-mail address: oladipooladapoo@gmail.com (O.O. Oladipo).
1
Moses O. Asamu and Oladapo O. Oladipo made equal contribution to the manuscript.

https://doi.org/10.1016/j.brainres.2023.148589
Received 8 June 2023; Received in revised form 3 September 2023; Accepted 18 September 2023
Available online 20 September 2023
0006-8993/© 2023 Elsevier B.V. All rights reserved.
M.O. Asamu et al.
AD (Alonso et al., 2001; Amor and Woodroofe, 2014; Anderson et al.,
2014). Aggregation of both proteins, beta-amyloid (Aβ) and tau, syn­
ergistically contributes to the loss of neuronal connections at synapses
and damage to the neurons in the brain tissue. These, in turn, induce and
promote cognitive decline in people with AD (Agnes et al., 2013). In AD
degeneration, microtubule motor proteins, phosphatase and kinase
mechanisms are dysregulated (Apostolova, 2016; Ashutosh et al., 2011).
Other dysregulated proteins or genes in AD include presenilins (PS-1 and
PS-2), amyloid precursor protein (APP), and secretases (Ávila-Villa­
nueva et al., 2022). Each of these factors either upregulates tau hyper­
phosphorylation into NFTs or increases Aβ production, which results in
the neurodegenerative changes observed in AD (Apostolova, 2016;
Ashutosh et al., 2011; Ávila-Villanueva et al., 2022).
The role of T lymphocytes – the adaptive immune cells – in the
pathogenesis of AD has not been extensively explored and reported.
Unlike the innate immune cells, astrocytes and microglia, which are
activated by the protein buildup in AD to produce inflammatory and
neurotoxic factors that, in turn, increase abnormal amyloid precursor
protein (APP) cleavage, production of Aβ and the phosphorylation of tau
according to mice study (Baek et al., 2016). An alteration in the function
of lymphocytes in AD may contribute to disease progression (Baik et al.,
2014). A study reported the presence of T-cells in the brain during
postmortem examination of AD patients (Bartholomäus et al., 2009).
Following an increase in the blood–brain barrier’s (BBB) permeability,
Dai and Shen (2021) stated that there is an increased T-cell influx into
the brain’s parenchyma, promoted by the increased expression of che­
mokine receptors by peripheral T-cells (Baruch et al., 2016). These re­
ceptors include C-C motif chemokine receptor type 2 and 5 (CCR2 and
CCR5) and C-X-C motif chemokine receptor 2 (CXCR2). Aβ also pro­
motes the infiltration of T-cells through BBB and dysfunction in T-cell
activation and presentation of antigens (Baruch et al., 2015), further
contributing to the inability to clear Aβ by the immune cells (Baik et al.,
2014).
The effect of chronic T-cells activation on neuroinflammation has
been well studied [12, see below]. T-cells dysfunction in AD contributes
to neuroinflammation by secreting pro-inflammatory mediators, which
have been reported to be an essential modulator in the pathogenesis of
this neurodegenerative disorder (Baruch et al., 2016). Increased CD4 +
T cell count has also been reported to upregulate the risk of developing
AD (Bateman et al., 2012). In this review, we discussed NFT and Aβ
plaques as the defining agents of AD, and we also discussed the struc­
tural and functional changes in the BBB associated with AD. We
reviewed T lymphocytes’ role in AD pathogenesis, including the role of
CD4 + and CD8 + T lymphocytes. Understanding these concepts is
germane in managing AD and its therapeutic research.
2. Onset, Etiology, and progression of AD
AD incidence and risk are directly associated with aging, increasing
exponentially after age 65 (Bettcher et al., 2021). The onset of AD is
often classified into two. Defined as the onset of AD before age 65, early-
onset AD comprises about 5% to 6% of AD cases (Blair et al., 2015),
while late-onset AD, i.e. occurring above age 65, makes up the majority
of AD cases. The majority of the early-onset cases of AD are familial; the
incidence of AD in two or more members of a generation. The early-
onset AD has been identified to pose an increased incidence of trau­
matic brain injury, impaired mental functions, reduced impairment in
memory, and a more aggressive course than late-onset AD (Blair et al.,
2015). Other distinctions between early-onset AD and late-onset AD
include the increased incidence of tau burden, alterations in the
connection of the frontoparietal network, and atrophy in the posterior
neocortex. This classification, which is still used to date in both research
and clinical trials, may not mirror the underlying etiology of AD. Ac­
cording to the review by Reitz et al. (2020), this gap in correlation is
evidenced by the incidence of late-onset cases in multiplex families with
early-onset AD and only a small percentage of early-onset AD being
2
Brain Research 1821 (2023) 148589
accounted for by known mutations (Bondi et al., 2017).
The etiology of AD has yet to be clearly understood, although risk
factors like aging, vascular diseases, head injuries, genetic factors, in­
fections and environmental factors have been identified (Breijyeh and
Karaman, 2020). Brain aging, a complex and irreversible process char­
acterized by atrophy, synaptic loss, enlargement of the ventricles,
deposition of NFTs, and cognitive decline, among other characteristics,
is a significant risk factor (Breijyeh and Karaman, 2020; Browne et al.,
2013). Genetic factors also play significant roles in AD etiology. Ac­
cording to twin and family studies, up to 80% of all AD cases had
phenotypic variance that was correlated to genetic factors (Cao and
Zheng, 2018). The late-onset AD is assumed to be caused by both
environmental (about 30%) and genetic factors (about 70%) (Carrano
et al., 2012). High levels of NFTs and Aβ plaques have also been iden­
tified as the pathological hallmarks of AD, and several therapeutic
studies on AD have been based on these hypotheses. However, there is
still no accepted theory for the pathogenesis of AD.
The pre-clinical stage of AD, which is also known as the pre-
symptomatic stage, does not present any symptom of AD nor impair­
ment in the performance of day-to-day activities but is marked by mild
memory loss and the onset of pathological impairment in the cortex and
hippocampus (Carrano et al., 2011; Cavanagh and Wong, 2018). This
stage is followed by a mild or early stage AD, which presents symptoms
like a mild decline in concentration and memory, mood swings and
depression, and disorientation of place and time (Cebrián et al., 2014).
These symptoms lead to difficulties in carrying out daily activities and
are followed by the spread of the disease to areas of the cerebral cortex
that result in increased impairment in memory, speech, writing, reading,
and loss of impulse control (Breijyeh and Karaman, 2020). This stage is
known as moderate AD and progresses into severe AD or late stage. The
late-stage AD is characterized by the spread of the disease to all cortical
areas, severe accumulation of NFTs and senile plaques that result in
progressive cognitive and functional decline and, eventually, death
(Carrano et al., 2011; Chabran et al., 2020).
3. Aβ, Tau-Protein buildup and neuroinflammation
Aβ and tau-protein are the pathological hallmarks of AD. This is
portrayed by the accumulation of amyloid plaques and NFT deposits in
the cerebral cortex and specific subcortical regions, which result in
parieto-temporal degeneration that extends to part of the cingulate
gyrus and frontal cortex (Cheng et al., 2014). Masters and Selkoe (2012)
reiterated that the cerebral deposit of Aβ in the areas of the brain
responsible for cognition and memory is a defining characteristic of AD
(Chui and Dorovini-Zis, 2010). Also, several studies have suggested that
AD pathological diagnosis is defined by the deposit and accumulation of
extracellular Aβ plaques (with Aβ42 amyloid protein being the main
constituent) and intracellular NFT of hyperphosphorylated tau-protein,
which binds to microtubules (Fig. 1) (Ciccocioppo et al., 2019; Cipollini
et al., 2019; Cohen and Torres, 2019). Predominant evidence-based
hypotheses on the aetiology of AD have been based on amyloid
cascade and tau-protein hyperphosphorylation, while others include
Apolipoprotein E and neuroinflammation hypotheses (Baruch et al.,
2016). In healthy humans, APP cleaved by enzymes like beta-site AβPP-
cleaving enzyme (BACE1) and gamma-secretase is involved in signal
transduction, migration of cells, and elongation of axons. At the same
time, its C-terminus is critical to gene expression and survival of the
neuronal cell (Ávila-Villanueva et al., 2022). However, APP mutations
or mutations in either of two APP cleavage enzymes, presenilins 1 (PS1)
or presenilin 2 (PS2), are associated with familial early-onset AD (Cic­
cocioppo et al., 2019). By identifying this mutation, there was a hy­
pothesis that Aβ causes AD, forming the basis of the amyloid cascade
experiment (Crews et al., 2010). This discovery drove research attention
to Aβ. The amyloid cascade hypothesis includes a sequence of events, of
which abnormal APP cleavage is key (Croese et al., 2021). The abnormal
cleavage of this amyloidogenic transmembrane protein results in the
M.O. Asamu et al.
Fig. 1. Tau-protein aids microtubule stabilization by promoting tubulin packaging into the microtubule in the healthy neuron (Dai and Shen, 2021). However, with
increase in the aggregation of Aβ plaques in Alzheimer’s disease, tau-protein becomes hyperphosphorylated, dissociate from microtubule, and aggregates into
neurofibrillary tangle (Dionisio-Santos et al., 2019). Due to these alterations, synaptic damage and neuronal death is induced. Also, there is atrophy in the cerebral
cortex and hippocampus (Dong and Benveniste, 2001), as well as a resultant enlargement of the ventricles in Alzheimer’s disease.
production of excessive Aβ and the formation of oligomers and subse­
quently result in the buildup and aggregation of Aβ in the brain tissue
(and CNS). Aβ oligomerization induces a sequence of events that causes
loss of synaptic communication, dysfunction of cholinergic neurons, and
synaptic degeneration. These further cause neuroinflammation, oxida­
tive stress, activation of tauopathy, death of neurons, and eventually,
impairment in cognition (Dá Mesquita et al., 2016).
In the review by Medeiros et al. (2010), tau-protein was described as
a protein associated with microtubules, found majorly in the axons
interacting with and aiding the assemblage of tubulin into the micro­
tubule for stabilization (Fig. 1) (Dai and Shen, 2021). Also reiterated was
that the phosphorylation of the protein prevents acute neuronal
apoptosis by stabilizing β-catenin. Tauopathies in neurodegeneration
are a result of the alteration in the ratio of 3R and 4R tau (existing as 1:1
in the normal human brain), leading to impairment in the ability of tau
to interact with microtubules, and there is abnormal phosphorylation of
tau residues (Dai and Shen, 2021). With the dysregulation of microtu­
bule motor proteins, phosphatase, and kinase mechanisms, the hyper­
phosphorylation of tau-protein, which upregulates its resistance to (and
degradation by ubiquitin-proteosome pathway) neutral proteases acti­
vated by calcium, results in fibrillization and accumulation into NFTs
(Apostolova, 2016; Ashutosh et al., 2011; Dani et al., 2018; Dansokho
et al., 2016; Deczkowska and Schwartz, 2018; DeMaio et al., 2022).
There is evidence that tau-hyperphosphorylation is induced by Aβ,
glucose impairment in the brain, and inflammation (Dai and Shen,
2021). In Aβ-induced dysfunction in synapses, including dendrite dys­
regulation, abnormal tau-protein phosphorylation is an important
mediator (De-Paula et al., 2012; DeTure and Dickson, 2019). With the
increase in Aβ, a sequence of events, which forms the basis of the tau
hypothesis, is initiated. Hyperphosphorylation of tau-protein is induced,
and the hyperphosphorylated tau dissociates from microtubules, accu­
mulates into NFTs and induces neuronal dysfunction and, ultimately,
death of the neurons (Dionisio-Santos et al., 2019). The buildup of
hyperphosphorylated tau correlates better with impairment in cognition
compared to Aβ buildup, inferred from a study that showed a higher-
paced decline in cognition and dysfunctional synaptic plasticity in AD
3
Brain Research 1821 (2023) 148589
patients with low Aβ and high tau-protein levels (Dionisio-Santos et al.,
2019; Dong and Benveniste, 2001). This hypothesis made hyper­
phosphorylated tau and associated NFT budding targets in AD thera­
peutic research in addition to the initial research focus on Aβ (Dionisio-
Santos et al., 2019).
Aβ and NFT are associated with activated microglia cells, markers of
neuroinflammation (Dong et al., 2019; Dorszewska et al., 2016).
Elevated inflammatory cytokines like interleukin 6, 8 and tumor ne­
crosis factor-α are released in response to glial activation as observed in
postmortem studies (Dubois et al., 2016; Duffy et al., 2018; Dutra et al.,
2013). It has been suggested that these pro-inflammatory cytokine levels
can be elevated by Aβ and tau-protein, according to in vitro studies
(Edwards, 2019; El Khoury et al., 2007).
A study aiming to assess the early relationship between brain Aβ, tau-
protein levels and neuroinflammation in cognitively normal older adults
using a comparative analysis of cerebrospinal fluid inflammatory
markers and PET Aβ and tau-protein levels suggested, in agreement with
several lines of previous research, that AD hallmark proteins and neu­
roinflammation share a dynamic relationship (Engelhardt et al., 2017).
Several studies have reported that postmortem and cerebrospinal fluid
(CSF) markers of activated microglia are increased in patients with AD
(Engelhardt et al., 2017; Erickson and Banks, 2013; Erickson et al.,
2014; Fan et al., 2017).It has been suggested that CSF levels of both
activated microglia and phosphorylated tau are associated (Fani et al.,
2021). At the same time, tau-protein and Aβ are usually colocalized with
these activated glial cells, evidenced in postmortem tissue, AD models,
and in vivo positron emission tomography studies (Engelhardt et al.,
2017; Ferretti et al., 2016; Fiala et al., 2005; Fisher et al., 2014;
Frackowiak et al., 1992; Fransen et al., 2020; Garbuz et al., 2021). This
inference correlates with a positron emission tomography study of 43
mild cognitive impaired (MCI) subjects over 2 years, which revealed that
low baseline MCI cases with increasing Aβ load had correlated microglia
activation levels that subsequently decline as Aβ reaches AD levels
(Dong et al., 2019). However, it was also reported that with the for­
mation of tau tangles in Aβ positive MCI subjects, there was a corre­
sponding increase in observed neuroinflammation (Dong et al., 2019).
M.O. Asamu et al.
Hence, with diverse research identifying neuroinflammation as a key
factor in the pathogenesis of AD, it gives new direction to explore in
therapeutic AD research (Gate et al., 2020).
4. Vascular dysfunction and BBB disruption in AD
In the brain of AD patients, there are several reported structural and
functional changes. The hippocampus and other brain areas involved in
spatial orientation and cognition have received significant research
attention in the study of AD (Dionisio-Santos et al., 2019). Neocortical
atrophy (which commences at the hippocampus and entorhinal cortex),
with increased synaptic and neuronal loss, is a marked pathological
change observed in AD (Gatz et al., 2006). It spreads into the association
cortices in the temporal, parietal and frontal lobes. Atrophy of the brain,
focusing on the medial temporal lobe and local changes in brain me­
tabolites, are structural changes in observed AD (Gendelman and Mos­
ley, 2015; Goverman, 2009).
In addition to tau and Aβ aggregation, vascular dysfunctions
contribute to neuronal loss and decline in cognition apparent in AD
(Guerreiro and Bras, 2015). There are reports that vascular dysfunction
promotes AD onset and progression (Hamelin et al., 2016). Vascular
biomarkers observed before marked cognitive decline in AD are a
decrease in Aβ42 and an increase in tau levels in the CSF (Harry, 2013).
The neurovascular unit comprises the blood–brain barrier (BBB),
smooth muscle cells in the walls of the blood vessels, pericytes, neurons,
and neuroglia (Hamelin et al., 2016). Decrease in the expression of
zonaoccludens protein 1 (ZO1) and occludin, a sealing protein molecule
of tight junction that anchors it with the adjacent plasma membrane, in
vascular endothelial cells progressively increases BBB permeability in
AD (Heneka et al., 2015; Heneka et al., 2010; Herrera CA, Prince M,
Knapp M, Karagiannidou M, and Guerchet M.World Alzheimer Report,
2016). BBB disruption at the hippocampus was observed in an MRI
image of a patient with mild cognitive decline (MCI) in a blood–brain-
CSF directional pathway of the contrast agent (Hickman et al., 2018).
In comparison, BBB disruption was observed before the atrophy of
the hippocampus (Höftberger et al., 2004). This observation suggests
that BBB disruption occurs before the observed neurodegenerative
decline in AD. Cerebral amyloid angiopathy (CAA), a vascular
dysfunction marked by the deposit of Aβ in cerebrovasculature, and
neuroinflammationare characteristics of AD pathology (Hamelin et al.,
2016). Neuroinflammation is stimulated by microglial and macrophages
of the innate immune cells, with contributions from the circulating
immune cells (Hamelin et al., 2016). CAA is an important cause of BBB
disruption. Factors contributing to BBB disruption, like degeneration of
endothelial cells, smooth muscle and pericytes, have been linked to CAA
(Hopperton et al., 2018). Aβ binds to receptors for advanced glycation
end product in a process that produces reactive oxygen species and
causes disruption in the tight junction between endothelial cells to
disrupt the integrity of the BBB (Iqbal et al., 2009). Thus, it makes Aβ
toxic to the endothelial cells of the brain, in vitro. Blair et al. (2015)
posited that tau-protein dysfunction also contributes to BBB disruption.
The report further explains that the infiltration of perivascular tau-
protein to the region of hippocampal blood vessels correlates with the
disruption of BBB (Ismail et al., 2020). Multiple neurodegenerative
pathways can be activated by disruption in the continuous pericyte and
astrocyte sheathed mono-layered endothelium of the BBB, which will
permit the influx of neurotoxic cells and other molecules, including
microbes, debris, and others, involved in neuroinflammatory and im­
mune responses into the brain (Guerreiro and Bras, 2015).
Generally, in AD pathology, the disruption of BBB modulates the
clearance of Aβ; causes impairment of tight junction, pericyte, and
endothelial cells; activates neuroglia cells; and permits the influx of
leukocytes, including cytotoxic T-cells, into the brain (Hamelin et al.,
2016). While this BBB breakdown ultimately results in inflammation,
damage to the neurons and synapses, and loss of neuronal connection. In
AD neuropathology, vascular dysfunction is a hallmark disease that
4
Brain Research 1821 (2023) 148589
worsens with disease progression (Guerreiro and Bras, 2015).
5. Role of brain resident and peripheral innate immune cells in
neuroinflammation and AD
Microglia is the most abundant immune cell in the brain and con­
stitutes more than 80% of brain-resident immune cells. Microglia are
indispensable to cerebral circuit development and synaptic hemody­
namics in the normal brain (Ittner and Götz, 2011; Ittner et al., 2010).
These cells play essential roles in presynaptic microenvironment im­
mune surveillance and modulate phagocytic and proteolytic processes,
which control axonal and dendritic terminal pruning (Iturria-Medina
et al., 2016). Through their numerous receptors, microglial cells sense
exogenous and endogenous insults to the CNS and respond by initiating
immune processes. They also maintain brain homeostasis and the plas­
ticity of neural pathways by remodeling synapses (Jahn, 2013). Micro­
glia carry out these processes by releasing trophic factors such as brain-
derived neurotrophic factors (Janelidze et al., 2018). Microglia become
activated, migrate to the lesion site and initiate an immune response
when exposed to pathological triggers (protein aggregates or neuronal
death) (Ji et al., 2013). Activated microglia takes one of two phenotypes:
the pro-inflammatory (M1) phenotype that secretes pro-inflammatory
cytokines such as interleukin-12, interleukin-1β, and tumor necrosis
factor-α, or the anti-inflammatory (M2) phenotype that secretes anti-
inflammatory cytokines such as interleukin-10, interleukin-13 and
interleukin-14 (Kawakami et al., 2004).
Microglia express immune-related receptors such as chemokine,
pattern recognition, and cytokine receptors, which interact with pro-
inflammatory signals and activate microglia (Kebir et al., 2007).
Several studies have linked microglia activation with the onset and
progression of neurodegenerative disorders (Janelidze et al., 2018;
Kawakami et al., 2004; Kelly et al., 2013). Studies in experimental AD
models have revealed microglia’s protective tendency in neuro­
degeneration. These studies reported the ability of microglia to surround
amyloid plaque through chemotaxis and clear the plaque by suppressing
its growth and accumulation in extracellular spaces (Kessler et al., 1998;
Kierdorf and Prinz, 2013). However, this effect is transient as the con­
stant alteration in brain homeostasis characteristic of AD leads to the
accumulation of Aβ. Accumulated Aβ can gain resistance to microglia-
induced elimination and degradation (Kivisäkk et al., 2006). The accu­
mulated Aβ primes and activate microglia; activated microglia take an
inflammatory phenotype and amplify the ongoing neuroinflammation
(Knezevic et al., 2018; Koch et al., 2016). The constant exposure to in­
flammatory factors and Aβ promotes the functional impairment of
microglia in AD (Kessler et al., 1998). Accumulated Aβ initiates neuro­
inflammatory and neurodegeneration by priming microglia and sup­
pressing the release of anti-inflammatory cytokines (Koch et al., 2016;
Konjevic Sabolek et al., 2019).
Microglia activation is a typical and key hallmark of the patho­
physiology of AD (Koch et al., 2016; Konjevic Sabolek et al., 2019). In
CK-p25 mice, the activation of microglia has been shown to correspond
with neurodegeneration through single-cell level RNA sequencing
(Korin et al., 2017). Through the upregulation of the expression of pro-
inflammatory factors such as macrophage migration inhibitory factor
and tumor-necrosis factor-α, microglia enhanced inflammation as early
as Aβ production. This shows the potential of microglia activation dur­
ing neurodegeneration to initiate and propagate neuronal loss and
cognitive dysfunction (Korin et al., 2017). Chronic microglia activation
can also cause the accumulation of p-Tau within nerves (Kovac et al.,
2011). This accumulation of p-Tau initiates a form of positive feedback
in which the accumulation of p-Tau enhances the activation and pro-
inflammatory phenotype of microglia (Krishnan et al., 2019; Kumar
et al., 2012). This process eventually activates a vicious cycle of neu­
rodegeneration, neuroinflammation, pro-inflammatory activation of
microglia, and accumulation of p-Tau through the induction of neuronal
p38-mediated mitogen-activated protein kinase signaling (Kuyumcu
M.O. Asamu et al. Brain Research 1821 (2023) 148589

et al., 2012). T cells can activate both microglia and astrocyte. T cell
participates in the activation of astrocyte and promotes neuro­
inflammation. Interferon- γ secreted by T cells induces astrocyte pro­
liferation and brain-reactive astrogliosis (Lassmann, 2018). Also, the
interleukin-17 secreted by Th-17 cells activates astrocytes by regu­
lating several signaling pathways in astrocytes. The cytokine controls
the expression of macrophage inflammatory proteins-1α (MIP-1 α)
through PI3K/Akt and NF-κB signaling pathways, stimulates the acti­
vation of inducible nitric oxide synthase, and promotes the signaling of
interleukin-6 (Laurent et al., 2017; Laurent et al., 2018).
Neutrophils which serve as the body’s first line of immune defense,
have been shown to infiltrate the brain of AD patients and animal
models of AD (Leng et al., 2023; Li et al., 2009; Liu and Wang, 2009).
Neutrophil: lymphocyte ratio in peripheral blood has also been linked
with cognitive decline in AD (Lowther and Hafler, 2012; Lue et al.,
2001). Neutrophils contribute to AD via several mechanisms. Neutro­
phils are involved in the BBB impairment, intravascular adhesion, and
brain infiltration characteristic of AD (Leng et al., 2023). Infiltrating
neutrophils produce interleukin-17, which promotes neurodegeneration
and BBB impairment (Lueg et al., 2015). Neutrophils also contribute to
neurotoxicity by forming neutrophils extracellular traps and producing
myeloperoxidase (Leng et al., 2023). The role of neutrophils in AD was
further buttressed when depletion of neutrophil infiltration was shown
to suppress microglial activation and amyloid plaque burden in mouse
models of AD (5XFAD and 3xTg mice). This study also reported better
performance in the cognitive ability test – the Y-maze spontaneous
alternation task (Leng et al., 2023).
Monocytes are another innate immune cell that has been implicated
in AD pathogenesis. Monocytes have been shown to infiltrate the brain,
suppress Aβ accumulation and improve cognitive function in transgenic
mouse models – APP/PS1 and 5xFAD (Ma X, Reynolds SL, Baker BJ, Li X,
Benveniste EN, Qin H. IL-17 enhancement of the IL-6 signaling cascade
in astrocytes. J Immunol., 2010; Machado-Santos et al., 2018). The
infiltration of monocytes into the brain is facilitated by C-C motif che­
mokine receptor 2 (CCR2). Blockade of the chemokine receptor has been
shown to limit the protective effect of monocyte. In a transgenic mouse
model, the blockade of CCR2 increased Aβ accumulation and promoted
memory loss (Machhi et al., 2021; Machhi et al., 2016). Monocytes are
crucial to the clearance of vascular Aβ in AD. Monocytes infiltrate the
luminal walls of Aβ + veins, internalize Aβ, and return to circulation
(Machhi et al., 2020). Evidence suggests a protective role of monocyte
and a therapeutic tendency in targeting monocyte. However, the pro-
inflammatory landscape of AD limits phagocytic capacity and directly
impairs the monocyte’s ability to eliminate cerebral deposits of Aβ
(Machhi et al., 2017). This constraint has been observed in human
studies of AD where the Aβ uptake and phagocytosis capacity of pe­
ripheral monocytes was impaired (Machhi et al., 2017).
6. Role of T lymphocytes in AD
The brain is immunologically active in the physiological state and
adequately protected by resident and infiltrating peripheral immune
cells (Ismail et al., 2020). Although present in low quantities at the
physiological state, adaptive immune cells (T and B cells) can infiltrate
the meninges and reside in the dura (Fig. 2). These adaptive immune
cells play critical roles in brain homeostasis and are involved in spatial
learning and neuronal development (Malm et al., 2010). The cytokines
(interleukin-4, interleukin-17, and interferon-γ) released by these cells
play a crucial role in brain homeostasis (Malm et al., 2005). The adap­
tive cells located in the choroid plexus, meninges, and other brain tissues
serve a neuroprotective purpose or instigate neurodegeneration
depending on the local environment (Marco and Skaper, 2006; Masters
and Selkoe, 2012). Brain-resident immune cells, microglia, were initially
thought to be solely responsible for the neuropathology of AD, but

Fig 2. The role of adaptive immune systems in brain homeostasis. There is homeostasis in healthy brain tissue. This homeostasis is characterized by a balance in the
activities of neurons, peripheral immune cells and brain resident immune cells (microglia and astrocytes). The brain resident immune cells are quiescent and are
called resting microglia and resting astrocytes. The peripheral immune cells such as antigen-presenting cells are also quiescent. Due to this balance, the brain is
devoid of inflammation and functions optimally (Ismail et al., 2020; Malm et al., 2010).

5
M.O. Asamu et al. Brain Research 1821 (2023) 148589

recent research has shown crosstalk between microglia and peripheral
immune cells in AD neuropathology (Mathys et al., 2017; Mattson,
2002; McGeer and McGeer, 2013; Medana et al., 2000; Medeiros et al.,
2011; Melzer et al., 2009). The interaction between innate and adaptive
immunity is critical in neuroprotection, neuroinflammation, and neu­
rodegeneration (Medana et al., 2000). Microglia interacts with both the
pro-inflammatory and anti-inflammatory arms of the adaptive immune
system, and this crosstalk fine-tunes the activities of microglia in return
(Medana et al., 2000; Croese et al., 2021).
As the adaptive immune system can facilitate both neuroprotection
and neuropathology, there is a need to balance its pro-inflammatory and
anti-inflammatory signaling to ensure brain homeostasis and protection.
While in the brain, T lymphocytes (CD4 + and CD8 + T cells) have two
fates. If the T cells fail to recognize an antigen and are not activated, they
migrate back to the periphery through the CNS lymphatic system. Due to
their failure to recognize the cognate antigen, the T cells do not cross the
BBB and eventually undergo apoptosis (Mendez, 2019; Merlini et al.,
2018). However, if they are activated by the binding of a cognate anti­
gen with their receptor, they initiate an effector immune reaction
(Meuth et al., 2009; Michaud et al., 2013). The effector immune reaction
develops into a neuroinflammatory condition that alters the secretory
ability and permeability of the BBB (Mietelska-Porowska and Wojda,
2017). The compromised BBB alters cytokine responses and facilitates
the massive infiltration of immune cells into the brain, amplifying the
ongoing neuroinflammation (Masters and Selkoe, 2012; Mittal et al.,
2019; Mokhtar et al., 2013; Mondragón-Rodríguez et al., 2020). T cells
control neurohomeostasis via a cascade of secretory molecules and im­
mune signals (Montagne et al., 2015). At the physiological level, all
subtypes of CD4 + T cells participate in neurohomeostasis and
contribute significantly to its maintenance. However, the subtypes play
diverse roles during neurodegeneration, which may either facilitate
neuroprotection or neurodegeneration (Monteiro et al., 2016).
6.1. Role of CD4 + T lymphocytes in AD
Both astrocytes and microglia are involved in the activation and
differentiation of T cells. They regulate the differentiation of CD4 + T
cells by modulating cytokines and molecules involved in the process.
They modulate the expression of molecules such as interleukin-6,
interleukin-10, interleukin-1, tumor necrosis factor-α, and trans­
forming growth factor-β responsible for the differentiation of regulatory
T cell (Treg) and effector T cells (Teff) (Morales et al., 2013; Morris et al.,
2019). While Teff secretes pro-inflammatory cytokines such as inter­
feron-γ, granzyme B, and interleukin-17, which promote pro-
inflammatory microglia phenotypes, Treg secretes anti-inflammatory
cytokines and promotes neuroprotection (Fig. 3) (Lueg et al., 2015;
Mount et al., 2007). Treg is crucial to immune tolerance. This subtype of
T cells prevents effector immune action against a wide array of antigens
such as self-antigens, environmental antigens, and bacterial antigens
(Mundt et al., 2019; Murphy and LeVine, 2010). In addition to sup­
pressing effector immune action, Treg regulates the proliferation of Teff
via the secretion of immunosuppressive cytokines that initiates
apoptosis and cytotoxicity.
Several studies and cumulative evidence have suggested the role of T
lymphocytes in neurodegeneration, such as AD (Bartholomäus et al.,
2009; Naert and Rivest, 2011; Nazem and Mansoori, 2008). Post-

Fig 3. The role of CD4 + T cells in Alzheimer’s disease. Activated antigen presenting cells present misfolded self-antigens to CD4 + T cells through major histo­
compatibility complex. Upon the recognition cognate antigen, CD4 + T cells differentiate into effector or regulatory subtype. The effector subtype, such as Th-1, Th-2
and Th-17, produced proinflammatory and neurotoxic cytokines that promote the transition of resting microglia into activated state. This phenomenon sustains and
enhances neuroinflammation and progression of Alzheimer’s disease. On the contrary, the regulatory subtype, Treg, produces anti-inflammatory cytokine to inhibit
antigen presentation and neuroinflammation (Mundt et al., 2019; Parbo et al., 2017; Parkhurst et al., 2013; Prinz and Priller, 2017).

6
M.O. Asamu et al.
mortem analysis of the brain of AD patients revealed a high number of
CD4 + and CD8 + T cells compared with control patients (Bartholomäus
et al., 2009; Naert and Rivest, 2011; Nazem and Mansoori, 2008). The
infiltration of a high number of T cells into the brain has been reported in
animal models of AD with mutations of APP and Aβ (Nilson et al., 2017;
Nordengen et al., 2019; Oberstein et al., 2018). There was also an
elevation in the expression of endothelial adhesion molecules, ICAM-1,
and vascular cell adhesion protein 1 (VCAM-1) (Baruch et al., 2015;
Nordengen et al., 2019; Oberstein et al., 2018). A study conducted in the
3xTg mouse model reported high expression of α4-integrins on the
surface of peripherally circulating CD4 + T cells compared to the wild
type (Parbo et al., 2017). The α4β1 + CD4 + T cells were also shown to
infiltrate close to the VCAM-1 + cerebral vessels (Park and Kupper,
2015). This shows the significance of α4β1 integrin expression and the
signaling of VCAM to the infiltration of CD4 + T cells in the neuropa­
thology of AD. The signaling blockade between the two was also shown
to impair leukocyte adhesion to blood vessels in the brain and improve
cognitive capacity (Park and Kupper, 2015). The alteration in BBB seen
in AD occurs during the early stages and facilitates the infiltration of all
subtypes of CD4 + T cells. The Treg infiltrating the brain confers neu­
roprotection during the early stages of AD but becomes less potent as the
disease advances. During the advanced stages of AD, Teff, such as helper
T cell-1 (Th-1) and helper T cell-17 (Th-17), secrete interferon-γ and
interleukin-17, respectively. These cytokines reduce Treg’s immuno­
suppressive capacity and cause immune tolerance breakdown (Mundt
et al., 2019; Parbo et al., 2017; Parkhurst et al., 2013).
T cells also influence neuroinflammation by regulating the secretion
of pro-inflammatory factors by myeloid cells such as dendritic cells and
macrophages. T cells control the secretion of tumor necrosis factor- α,
interleukin-1β, and interleukin-6 by these cells (Nilson et al., 2017). In
addition, T cells can initiate neuroinflammation directly in an MHC-II-
based manner. To achieve this, parenchymal T cells are activated and
infiltrate the brain after conventional dendritic cells present myelin
antigens to them (Pellicanò et al., 2012). The population of retinoic acid
receptor-related orphan nuclear receptor γt+ (RORγt + ) Th-17 T cells
increase significantly in AD compared to mild cognitive impairment and
age-matched healthy subjects (Perry and Holmes, 2014; Pietronigro
et al., 2019; Pirker-Kees et al., 2013; Prinz et al., 2011). RORγt + Th-17
cells majorly secrete interleukin-17, which has been shown to weaken
the tight junctions that form the BBB (Fig. 3). The compromised BBB has
altered permeability and allows for the mass migration of peripheral
immune cells into the brain tissues. Upon infiltrating the brain, the
immune cells produce inflammatory cytokines such as tumor necrosis
factor-α, interleukin-1β, and interleukin-6 that constitute an inflamma­
tory response in the brain (Prinz and Priller, 2017). The report of studies
in mouse models of AD has shown that Aβ promotes the infiltration of
Th-17 cells into the brain (Prinz and Priller, 2017; Rahman and Lendel,
2021; Ransohoff, 2016). More Th-17 cells infiltrated the hippocampus,
and there was a corresponding elevation in the expression of interleukin-
17 and interleukin-22 in the hippocampus, CSF, and peripheral blood
when Aβ was injected into the hippocampus (Prinz and Priller, 2017;
Rahman and Lendel, 2021; Ransohoff, 2016). The infiltration of Th-17
cells also caused neuronal apoptosis (Ransohoff, 2016).
Due to its regulatory capacity, Treg has been linked to several neu­
roinflammatory and neurodegenerative diseases, including AD. How­
ever, the role of Treg in neuroprotection and neurodegeneration is
controversial. Treg population is eit6her reduced or normal in AD and
has a proven neuroprotective function (Pirker-Kees et al., 2013; Prinz
et al., 2011; Reddy et al., 2018). Treg’s presence suppresses AD’s pro­
gression, and its absence leads to an accelerated decline in cognitive
capacity (Fig. 3) (Reitz et al., 2020). The abundance of Treg has been
shown to regulate the population and activities of microglia (Rizzo et al.,
2018). In APP/PS1 mice, a high level of circulating Treg slowed down
the decline in cognitive capacity and increased the microglia population
in the plaques. Treg also induced and promoted the conversion of
microglia from pro-inflammatory (M1) phenotype to anti-inflammatory
7
Brain Research 1821 (2023) 148589
(M2) phenotype. This process effectively suppresses neuroinflammation,
which is highly upregulated in AD (Rossi et al., 2011). Studies in mouse
models of AD have also shown the critical role played by CD4 + CD25 +
Treg in the progression of AD (Rossi et al., 2021; Salvador et al., 2021).
Treg coordinates immune tolerance, modulates immune responses,
suppresses AD neurodegeneration, and regulates the response of
microglia to amyloid deposition (Rizzo et al., 2018). Studies in mouse
models of AD have shown that the immunosuppressive role of Treg also
affects the phagocytic action of innate immune cells in the CNS and the
clearance of amyloid plaques (Rossi et al., 2021; Salvador et al., 2021).
In APP/PS1 mouse model, the depletion of Treg impaired the recruit­
ment of microglia for the clearance of Aβ plaque and promoted the
associated cognitive impairment. The subsequent treatment with low-
dose peripheral administration of interleukin-2 restored the recruit­
ment of microglia and improved cognitive capacity (Salvador et al.,
2021).
According to the study conducted by Baruch et al. 2015 there seems
to be a dichotomy between the role of Treg in brain tissues and those
circulating in peripheral blood in CNS disorders (Rossi et al., 2021). The
study reported a decrease in the circulating Treg while those in brain
tissues increased. However, the anti-inflammatory function of Treg in
AD was conserved. Based on the report from the study, the group sug­
gested transient depletion or pharmacological inhibition of peripheral
Treg to suppress neuroinflammation, reduce plaque formation, enhance
Aβ clearance, and improve cognitive capacity (Rossi et al., 2021).
Another study reported that depletion of peripheral circulating Treg
impaired the recruitment of activated microglia to amyloid deposits but
did not affect the clearance of Aβ by microglia (Salvador et al., 2021). In
the 5XFAD mouse model, the depletion of Treg promoted Aβ plaque
clearance and recruitment of immune cells via the choroid plexus (Rossi
et al., 2021). These studies and reports suggest that a reduction in the
population of circulating Treg may serve a neuroprotective function and
help to suppress the neuropathology of AD. There is a need for further
studies to explain the exact roles of Treg at each stage of AD neuropa­
thology, the mechanisms employed for these effects, and the potential
Treg-based therapeutic modulations.
Brain immune homeostasis and neuropathology during neuro­
degeneration are controlled by the crosstalk and interaction between
microglia and T cells (Sarlus and Heneka, 2017). The crosstalk between
infiltrating CD4 + T cells and microglia has been reported to serve a
crucial role in the immunoregulatory mechanisms involved in the
neuropathology of AD (Fig. 3) (Baek et al., 2016; Saunders et al., 2012).
Aβ-specific Th-1 cells induce major histocompatibility complex class II
(MHC II) + microglia, suppressing AD neuropathology in the 5XFAD
mouse model (Saunders et al., 2012). This effect was proposed as
interferon- γ signaling dependent (Fig. 3) (Saunders et al., 2012).
However, Aβ-specific Th-1 and Th-17 cells have a contrasting effect on
microglia in APP/PS1 mouse model. In this setting, Th-1 and Th-17 cells
increased β–amyloid plaque burden, neuroinflammation, microgliosis,
and cognitive impairment (Baek et al., 2016). The effect seen in APP/
PS1 mouse model may be due to the secretion of interferon-γ by Th-1
cells (Saunders et al., 2012). The interferon-γ secreted by Th-1 cells
can activate microglia and astrocytes, offsetting the brain’s immune
homeostasis, promoting Aβ deposition, and impairing cognitive func­
tions [142; 163]. These reports suggest that the role of Th-1 cells in AD is
based on the disease stage, and this could mean that manipulating Th-1
cells at a specific disease stage could be a viable therapeutic approach
for AD.
The infiltration of T cells into the AD brain correlates with the
abundance of p-tau. This has been observed in the medial frontal gyrus,
inferior parietal lobule, and middle temporal gyrus of AD patients
(Schlüter et al., 2001). Tau-dependent infiltration of T cells has also been
seen in the frontotemporal gyrus and hippocampus (Schwartz et al.,
2022). These observations confirm Tau’s contribution to AD patho­
physiology and the infiltration of T cells into the brain. However, the
molecular mechanisms responsible for this process have not been
M.O. Asamu et al.
identified.
6.2. Role of Cd8 + T lymphocytes in AD
Analysis of AD in patients and mouse models has implicated CD8 + T
cells in the neuropathology of AD (Fig. 4) (Baruch et al., 2015; Nazem
and Mansoori, 2008; Prinz et al., 2011; Sengupta et al., 1998). CD8 + T
cells are the predominant T cell in brain tissues associated with cognitive
functions. The CD8 + T cells are near neuronal processes and microglia
(Kumar et al., 2012; Machhi et al., 2021). A crucial link has also been
established between the infiltration of CD8 + T cells and tau pathology
in experimental animal models and patients (Nazem and Mansoori,
2008; Schwartz et al., 2022). Infiltration of CD8 + T cells into the AD-
affected brain tissues has been reported in both human and animal
model studies and has been linked with disease progression (Fig. 4).
These reports suggest the involvement of CD8 + T cells in AD neuro­
pathology (Bartholomäus et al., 2009; Sheng et al., 2001). Higher per­
centage of HLA-DR + CD8 + T cells actively secreting pro-inflammatory
cytokines have been revealed in the blood immune profiling of AD pa­
tients compared with healthy people (Prinz et al., 2011; Shipton et al.,
2011). This suggests the activation of circulating CD8 + T cells in the
blood of AD patients.
The CD8 + T cells observed during the analysis of AD-affected
hippocampi possess granules containing granzyme A (Prinz et al.,
2011). The peripheral blood of patients with AD or AD-like mild neu­
rocognitive disorder has been shown to have a high number of CD8 +
TEMRA cells that produce either interferon-γ or tumor necrosis factor-α
(Prinz et al., 2011). Subsets of CD8 + T cells that produce interleukin-17
have also been detected in the peripheral blood of AD patients. These
findings illustrate the active role of CD8 + T cells in AD pathogenesis and
cognitive impairment (Smolders et al., 2018). One of the significant
contributions of CD8 + T cells to neuropathology is the propagation of
Fig 4. The role of CD8 + T cells in Alzheimer’s disease. Upon presentation of cognate antigen to CD8 + T cells, they become activated, differentiate and expand.
Activated CD8 + T cells produce proinflammatory cytokines; interact and activate microglia; and promote neuroinflammation (Sarlus and Heneka, 2017; Weiss
et al., 2011).
8
Brain Research 1821 (2023) 148589
initial lesions (Stadelmann et al., 2008). The initial tissue damage in AD,
caused by inflammatory CD4 + T cells and neurotoxic Aβ or phos­
phorylated tau protein, is detected by myeloid cells, majorly microglia
(Sengupta et al., 1998). The microglia, in turn, become activated and
upregulated; and eventually produce pro-inflammatory cytokines and
chemokines that recruit CD8 + T cells (Sengupta et al., 1998; Starr et al.,
2009; Steinbach et al., 2018). While in the brain tissues, CD8 + T cells
can interact with several cell types with high expression of MHC-I in AD
(Stojić-Vukanić et al., 2020; Stojiljkovic et al., 2019). CD8 + T cells can
act directly on neurons and impair neuronal integrity through the
perforin-granzyme-dependent or Fas ligand-Fas receptor mechanisms
(Streit et al., 2004). They can also destroy myelin sheath and oligo­
dendrocytes, which compromises the neurons. This phenomenon is
termed “collateral injury” (Sweeney et al., 2018; Taipa et al., 2018). It is
worth noting that the activities of CD8 + T cells are also capable of a
“spillover” effect. A phenomenon in which “spillover” of cytotoxic
molecules from immunological synapses occurs after CD8 + T cells have
attacked and killed off several target cells. This phenomenon leads to the
unintended death of neighboring cells (Tang and Le, 2016).
Another mechanism of action of CD8 + T cells is the silencing of
neural electrical signaling. CD8 + T cells can cause massive perforin
insertion, forming an ion channel (Sweeney et al., 2018; Tiemessen
et al., 2007). This leads to an influx of Ca2+ ions and an elevation of
intracellular Ca2+ ion levels. The high intracellular Ca2+ ion level may
be further coupled with the release of glutamate by the activated CD8 +
T-cells (Sweeney et al., 2018; Tiemessen et al., 2007). CD8 + T cells can
also cause neuronal damage and cognitive impairment by secretion of
pro-inflammatory cytokines such as interferon-γ, tumor necrosis factor-
α, and interleukin-17. These cytokines are well capable of compromising
the BBB by impairing its permeability. With increased BBB permeability,
many T cells infiltrate the CNS parenchyma (Togo et al., 2002; Town
et al., 2005). The cytokines also upregulate MHC-I and sensitize
M.O. Asamu et al.
neuronal and non-neuronal cells to CD8 + T cells (Trajkovic et al.,
2001). They can also facilitate the direct killing of neuronal cells
(Tröscher et al., 2019). In animal models of AD, these cytokines have
been shown to promote synaptic plasticity and cognitive impairment by
upregulating the release of glutamate and the expression or phosphor­
ylation of glutamate receptors (Unger et al., 2020; Unger et al., 2018;
Vass and Lassmann, 1990).
CD8 + T cells communicate directly with several subsets of CD11b +
myeloid cells, including microglia (Villegas-Mendez et al., 2012). While
the action of CD8 + T cells is mainly towards a target cell, CD11b +
myeloid cells secrete a wide array of pro-inflammatory molecules
(reactive oxygen and nitrogen, and cytokines inclusive), which leads to
an attack on neighboring cells (which could include neurons) (Sarlus
and Heneka, 2017; Steinbach et al., 2018; Villegas-Mendez et al., 2012;
Wagner et al., 2020). This interaction between CD8 + T cells and
microglia that leads to the latter secreting pro-inflammatory cytokines
has been established in chronic infection (Wattmo et al., 2016). Mouse
model of experimental autoimmune encephalomyelitis (EAE) has been
used to show that CD8 + T cells employ Fas ligand-Fas receptor signaling
to interact with monocytes/monocyte-derived cells infiltrating the brain
(Webers et al., 2020). This phenomenon could also occur between CD8
+ T cells and microglia, leading to their activation and secretion of pro-
inflammatory mediators (Weiss et al., 2011). The interaction between
CD8 + T cells and myeloid cells in the brain tissues could be said to be a
hotspot in brain immunopathologies. In AD, the presence of CD8 + T
cells in the brain tissues could enhance the activation of microglia and,
in turn, promote AD progression (Wood et al., 1993).
The presence of tissue-resident memory cell-like CD8 + T cells in
hippocampi and subcortical white matter of animal models of AD and
AD patients suggests another form of CD8 + T cells in AD (Baruch et al.,
2015; Nazem and Mansoori, 2008; Wyatt-Johnson and Brutkiewicz,
2020; Xie and Yang, 2015). Tissue-resident memory cells highly express
inhibitory receptors, cytotoxic T-lymphocyte-associated protein-4
(CTLA-4) and programmed cell death-1 (PD-1), and have a reduced
capacity to produce cytotoxic enzymes (Mount et al., 2007; Murphy and
LeVine, 2010; Naert and Rivest, 2011; Nazem and Mansoori, 2008).
However, these cells can produce pro-inflammatory cytokines and may
induce the activation of myeloid cells when their inhibition is surpassed
by stimulatory signals (Wyatt-Johnson and Brutkiewicz, 2020; Yang
et al., 2013; Yang et al., 2013; Yong et al., 1991). This means tissue-
resident memory cells can influence the activational and functional
status of microglia and contribute to AD progression. However, there is
little evidence on this concept, and further research is needed to explain
this phenomenon.
6.3. Role of T cell in BBB disruption
The infiltration of T cells through the BBB is controlled by cytokines,
chemokines, and their receptors. Endothelial cells control the movement
of cytokines and chemokines between the brain and blood (Zenaro et al.,
2015). In AD, the expression of high levels of chemokine receptors such
as CXCR2, CCR5, and MIP-1 α leads to the movement of T cells through
the tight junctions of brain endothelium. This phenomenon was
confirmed in an animal model of AD where the accumulation of Aβ
upregulated the expression of RAGE and CCR5, which promoted T cell
infiltration into the brain (Park and Kupper, 2015). At the initial stage of
brain infiltration, immune cells bind with selectins present on endo­
thelial cells before crossing the endothelium and engaging chemokine
receptor CX3CR1 on endothelial cells. After engaging CX3CR1, immune
cells circulate against blood flow (Zenaro et al., 2017; Zhang et al.,
2013). The binding of immune cells with endothelial CXCR1, they
adhere to the endothelium by activating integrins expressed on their
surface. After the adhesion, immune cells undergo transendothelial
migration or extravasation and move directly to the site of inflammation
(Zenaro et al., 2017). This process is enhanced during AD as brain
amyloidosis activates and upregulates the expression of brain vessel
9
Brain Research 1821 (2023) 148589
adhesion molecules (Baruch et al., 2015). During AD, T cells are one of
the predominant cells infiltrating the brain through pathologically
altered BBB (Zhang et al., 2022). Several factors can promote the infil­
tration of T cells into the brain during AD. One of the factors is dendritic
cells that promote brain infiltration of Aβ-specific T cells (Zhao et al.,
2003). Aβ can also promote brain infiltration of T cells by initiating the
secretion of tumor necrosis factor-α by microglia and expression of
transforming growth factor-β1 by astrocytes (Zhao et al., 2018; Zotova
et al., 2013). Excessive secretion of transforming growth factor-β1 by
astrocytes can induce two contrasting effects. Transforming growth
factor-β1 can suppress the accumulation of Aβ and plaque formation. On
the contrary, transforming growth factor-β1 can promote brain
amyloidosis and enhance neuroinflammation (Zotova et al., 2013).
7. Concluding remarks
There is ample proof that neuroinflammation plays a part in the
development and progression of Alzheimer’s disease. Apart from the
roles of brain resident innate immune cells, microglia, in neuro­
inflammation, the adaptive immune system has also been implicated in
this process. Recent studies have shown the involvement of adaptive
immune cells, particularly T lymphocytes, in neuroinflammation and
neurodegeneration. The presentation and binding of T lymphocytes with
cognate antigens lead to their activation and clonal expansion into
effector subsets of CD4 + and CD8 + T cells that secrete pro-
inflammatory cytokines. The secretion of these cytokines exacerbates
neuroinflammation, which promotes several physiological and
morphological changes in the brain. T cell-induced neuroinflammation
alters the permeability of the BBB and promotes the buildup of NFT and
amyloid plaques. Understanding the role of adaptive immune cells and
the interplay between adaptive immune cells and brain-resident innate
immune cells in the pathogenesis and progression of AD will play a
crucial role in developing immunotherapies for AD. Targeting immune-
suppressive and anti-inflammatory subsets, such as Treg, could improve
immunoregulation and neuroprotection while preventing neuro­
inflammation and neurodegeneration. Also, the presence of inflamma­
tory mediators in CSF and blood; and changes in peripheral lymphocytes
can be used as biomarkers to diagnose AD early and monitor its
progression.
There is little information on each AD stage’s immune composition
and signature. This lack of characterization of the immune signature of
AD stages is mainly due to the inadequate recruitment and availability of
patients for such studies. To develop better biomarkers and immuno­
therapy for AD, there is a need to understand the immune mediators
present at the early, moderate, and late AD stages. Understanding the
activities of immune cells in AD has been challenging, and most of the
current information is obtained from mouse models. AD studies would
greatly benefit from developing model systems that recreate the activ­
ities of peripheral immune cells and vascular systems in human AD. Such
models could incorporate peripheral immune cells and vascular systems,
single-cell imaging, patient-derived cells, and in vitro three-dimensional
models with higher cellular complexity. Microfluidics, induced plurip­
otent stem cell-derived microglia and multicellular human models could
also be employed in dissecting immune signalling and cell interaction
involved in neurodegeneration.
CRediT authorship contribution statement
Moses O. Asamu: Conceptualization, Writing – review & editing.
Oladapo O. Oladipo: Conceptualization, Writing – review & editing.
Oluseun A. Abayomi: Writing and Proofreading. Afeez A. Adebayo:
Writing and Proofreading.
Declaration of Competing Interest
The authors declare that they have no known competing financial
M.O. Asamu et al.
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
No data was used for the research described in the article.
Acknowledgements
None.
Statements Declaration of interest
None.
Funding
Not applicable.
Ethical approval and consent to participate
Not applicable.
Consent for publication
All authors agree to the final manuscript.
References
Agnes, P., Christiane, S., Peter, D., 2013. T-Cells show increased production of cytokines
and activation markers in alzheimer’s disease. Brain. Disord. Ther. 3, 3–112.
Albrecht, D.S., Sagare, A., Pachicano, M., Sweeney, M.D., Toga, A., Zlokovic, B., Chui, H.,
Joe, E., Schneider, L., Morris, J.C., Benzinger, T., Pa, J., 2021. Early
neuroinflammation is associated with lower amyloid and tau levels in cognitively
normal older adults. Brain, Behavior, and Immunity 94, 299–307.
Alonso Adel, C., Mederlyova, A., Novak, M., Grundke-Iqbal, I., Iqbal, K., 2004. Promotion
of hyperphosphorylation by frontotemporal dementia tau mutations. The Journal of
Biological Chemistry 279 (33), 34873–34881. https://doi.org/10.1074/jbc.
M405131200.
Alonso, A., Zaidi, T., Novak, M., Grundke-Iqbal, I., Iqbal, K., 2001.
Hyperphosphorylation induces self-assembly of tau into tangles of paired helical
filaments/straight filaments. ProcNatlAcadSci U S A. 98 (12), 6923–6928. https://
doi.org/10.1073/pnas.121119298.
Amor, S., Woodroofe, M.N., 2014. innate and adaptive immune responses in
neurodegeneration and repair. Immunology 141 (3), 287–291. https://doi.org/
10.1111/imm.12134.
Anderson, K.M., Olson, K.E., Estes, K.A., Flanagan, K., Gendelman, H.E., Mosley, R.L.,
2014. Dual destructive and protective roles of adaptive immunity in
neurodegenerative disorders. Transl Neurodegener. 3 (1), 25. https://doi.org/
10.1186/2047-9158-3-25.
Apostolova, L.G., 2016. Alzheimer disease: CONTINUUM: Lifelong Learning in
Neurology 22 (2, Dementia), 419–434.
Ashutosh, Kou, W., Cotter, R., Borgmann, K., Wu, L.i., Persidsky, R., Sakhuja, N.,
Ghorpade, A., 2011. CXCL8 protects human neurons from amyloid-β-induced
neurotoxicity: Relevance to alzheimer’s disease. Biochemical and Biophysical
Research Communications 412 (4), 565–571.
Ávila-Villanueva, M., Marcos Dolado, A., Gómez-Ramírez, J., Fernández-Blázquez, M.,
2022. Brain structural and functional changes in cognitive impairment due to
alzheimer’s disease. Frontiers in Psychology 21 (13), 886619. https://doi.org/
10.3389/fpsyg.2022.886619.
Baek, H., Ye, M., Kang, G.H., Lee, C., Lee, G., Choi, D.B., Jung, J., Kim, H., Lee, S., Kim, J.
S., Lee, H.J., Shim, I., Lee, J.H., Bae, H., 2016. Neuroprotective effects of CD4+CD25
+Foxp3+ regulatory T cells in a 3xTg-AD alzheimer’s disease model. Oncotarget 7
(43), 69347–69357. https://doi.org/10.18632/oncotarget.12469.
Baik, S.H., Cha, M.Y., Hyun, Y.M., Cho, H., Hamza, B., Kim, D.K., Han, S.H., Choi, H.,
Kim, K.H., Moon, M., Lee, J., Kim, M., Irimia, D., Mook-Jung, I., 2014. Migration of
neutrophils targeting amyloid plaques in alzheimer’s disease mouse model.
Neurobiology of Aging 35 (6), 1286–1292. https://doi.org/10.1016/j.
neurobiolaging.2014.01.003.
Bartholomäus, I., Kawakami, N., Odoardi, F., Schläger, C., Miljkovic, D., Ellwart, J.W.,
Klinkert, W.E., Flügel-Koch, C., Issekutz, T.B., Wekerle, H., Flügel, A., 2009. Effector
T cell interactions with meningeal vascular structures in nascent autoimmune CNS
lesions. Nature 462 (7269), 94–98. https://doi.org/10.1038/nature08478.
Baruch, K., Rosenzweig, N., Kertser, A., Deczkowska, A., Sharif, A.M., Spinrad, A.,
Tsitsou-Kampeli, A., Sarel, A., Cahalon, L., Schwartz, M., 2015. Breaking immune
tolerance by targeting Foxp3(+) regulatory T cells mitigates alzheimer’s disease
10
Brain Research 1821 (2023) 148589
pathology. Nature Communications 18 (6), 7967. https://doi.org/10.1038/
ncomms8967.
Baruch, K., Deczkowska, A., Rosenzweig, N., Tsitsou-Kampeli, A., Sharif, A.M.,
Matcovitch-Natan, O., Kertser, A., David, E., Amit, I., Schwartz, M., 2016. PD-1
immune checkpoint blockade reduces pathology and improves memory in mouse
models of alzheimer’s disease. Nature Medicine 22 (2), 135–137. https://doi.org/
10.1038/nm.4022.
Bateman, R.J., Xiong, C., Benzinger, T.L.S., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.
S., Cairns, N.J., Xie, X., Blazey, T.M., Holtzman, D.M., Santacruz, A., Buckles, V.,
Oliver, A., Moulder, K., Aisen, P.S., Ghetti, B., Klunk, W.E., McDade, E., Martins, R.
N., Masters, C.L., Mayeux, R., Ringman, J.M., Rossor, M.N., Schofield, P.R.,
Sperling, R.A., Salloway, S., Morris, J.C., 2012. dominantly inherited alzheimer
network. Clinical and biomarker changes in dominantly inherited alzheimer’s
disease. The New England Journal of Medicine 367 (9), 795–804.
Bettcher, B.M., Tansey, M.G., Dorothée, G., Heneka, M.T., 2021. Peripheral and central
immune system crosstalk in alzheimer disease - a research prospectus. Nature
Reviews. Neurology 17 (11), 689–701. https://doi.org/10.1038/s41582-021-00549-
x.
Blair, L.J., Frauen, H.D., Zhang, B., Nordhues, B.A., Bijan, S., Lin, Y.C., Zamudio, F.,
Hernandez, L.D., Sabbagh, J.J., Selenica, M.L., Dickey, C.A., 2015. Tau depletion
prevents progressive blood-brain barrier damage in a mouse model of tauopathy.
Acta NeuropatholCommun. 31 (3), 8. https://doi.org/10.1186/s40478-015-0186-2.
Bondi, M.W., Edmonds, E.C., Salmon, D.P., 2017. Alzheimer’s disease: past, present, and
future. J IntNeuropsychol Soc. 23 (9–10), 818–831. https://doi.org/10.1017/
S135561771700100X.
Breijyeh, Z., Karaman, R., 2020. Comprehensive review on alzheimer’s disease: Causes
and treatment. Molecules 25 (24), 5789. https://doi.org/10.3390/
molecules25245789.
Browne TC, McQuillan K, McManus RM, O’Reilly JA, Mills KH, Lynch MA. IFN-γ
Production by amyloid β-specific Th1 cells promotes microglial activation and
increases plaque burden in a mouse model of Alzheimer’s disease. J Immunol. 2013
Mar 1;190(5):2241-51. doi: 10.4049/jimmunol.1200947.
Cao, W., Zheng, H., 2018. Peripheral immune system in aging and alzheimer’s disease.
Molecular Neurodegeneration 13 (1), 51. https://doi.org/10.1186/s13024-018-
0284-2.
Carrano, A., Hoozemans, J.J., van der Vies, S.M., Rozemuller, A.J., van Horssen, J., de
Vries, H.E., 2011. amyloid beta induces oxidative stress-mediated blood-brain
barrier changes in capillary amyloid angiopathy. Antioxidants & Redox Signaling 15
(5), 1167–1178. https://doi.org/10.1089/ars.2011.3895.
Carrano, A., Hoozemans, J.J., van der Vies, S.M., van Horssen, J., de Vries, H.E.,
Rozemuller, A.J., 2012. Neuroinflammation and blood-brain barrier changes in
capillary amyloid angiopathy. Neuro-Degenerative Diseases 10 (1–4), 329–331.
https://doi.org/10.1159/000334916.
Cavanagh, C., Wong, T.P., 2018. Preventing synaptic deficits in alzheimer’s disease by
inhibiting tumor necrosis factor alpha signaling. IBRO Reports 4, 18–21. https://doi.
org/10.1016/j.ibror.2018.01.003.
Cebrián, C., Loike, J.D., Sulzer, D., 2014. Neuronal MHC-I expression and its implications
in synaptic function, axonal regeneration and parkinson’s and other brain diseases.
Frontiers in Neuroanatomy 8, 114. https://doi.org/10.3389/fnana.2014.00114.
Chabran, E., Noblet, V., Loureiro de Sousa, P., Demuynck, C., Philippi, N., Mutter, C.,
Anthony, P., Martin-Hunyadi, C., Cretin, B., Blanc, F., 2020. Changes in gray matter
volume and functional connectivity in dementia with lewy bodies compared to
alzheimer’s disease and normal aging: implications for fluctuations. Alzheimer’s
Research & Therapy 6;12(1):9. https://doi.org/10.1186/s13195-019-0575-z.
Cheng, X., He, P., Yao, H., Dong, Q., Li, R., Shen, Y., 2014. Occludin deficiency with
BACE1 elevation in cerebral amyloid angiopathy. Neurology 82 (19), 1707–1715.
https://doi.org/10.1212/WNL.0000000000000403.
Chui, R., Dorovini-Zis, K., 2010. Regulation of CCL2 and CCL3 expression in human brain
endothelial cells by cytokines and lipopolysaccharide. Journal of Neuroinflammation
7, 1. https://doi.org/10.1186/1742-2094-7-1.
Ciccocioppo, F., Lanuti, P., Pierdomenico, L., Simeone, P., Bologna, G., Ercolino, E.,
Buttari, F., Fantozzi, R., Thomas, A., Onofrj, M., Centonze, D., Miscia, S.,
Marchisio, M., 2019. The characterization of regulatory t-Cell profiles in alzheimer’s
disease and multiple sclerosis. Scientific Reports 9 (1), 8788. https://doi.org/
10.1038/s41598-019-45433-3.
Cipollini, V., Anrather, J., Orzi, F., Iadecola, C., 2019. Th17 and cognitive impairment:
possible mechanisms of action. Frontiers in Immunology 13, 95. https://doi.org/
10.3389/fnana.2019.00095.
Cohen, J., Torres, C., 2019. Astrocyte senescence: Evidence and significance. Aging Cell
18 (3), e12937.
Crews, L., Rockenstein, E., Masliah, E., 2010. APP transgenic modeling of alzheimer’s
disease: mechanisms of neurodegeneration and aberrant neurogenesis. Brain
StructFunct. 214 (2–3), 111–126. https://doi.org/10.1007/s00429-009-0232-6.
Croese, T., Castellani, G., Schwartz, M., 2021. Immune cell compartmentalization for
brain surveillance and protection. Nature Immunology 22 (9), 1083–1092. https://
doi.org/10.1038/s41590-021-00994-2.
Dá Mesquita, S., Ferreira, A.C., Sousa, J.C., Correia-Neves, M., Sousa, N., Marques, F.,
2016. Insights on the pathophysiology of alzheimer’s disease: the crosstalk between
amyloid pathology, neuroinflammation and the peripheral immune system.
Neuroscience and Biobehavioral Reviews 68, 547–562. https://doi.org/10.1016/j.
neubiorev.2016.06.014.
Dai, L., Shen, Y., 2021. insights into t-cell dysfunction in alzheimer’s disease. Aging Cell
20 (12), e13511.
Dani, M., Wood, M., Mizoguchi, R., Fan, Z., Walker, Z., Morgan, R., Hinz, R., Biju, M.,
Kuruvilla, T., Brooks, D.J., Edison, P., 2018. Microglial activation correlates in vivo
M.O. Asamu et al.
with both tau and amyloid in alzheimer’s disease. Brain 141 (9), 2740–2754.
https://doi.org/10.1093/brain/awy188. PMID: 30052812.
Dansokho, C., Ait Ahmed, D., Aid, S., Toly-Ndour, C., Chaigneau, T., Calle, V.,
Cagnard, N., Holzenberger, M., Piaggio, E., Aucouturier, P., Dorothée, G., 2016.
Regulatory T cells delay disease progression in alzheimer-like pathology. Brain 139
(Pt 4), 1237–1251. https://doi.org/10.1093/brain/awv408.
Deczkowska A, Schwartz M. Targeting neuro-immune communication in
neurodegeneration: Challenges and opportunities. J Exp Med. 2018 Nov 5;215(11):
2702-2704. doi: 10.1084/jem.20181737.
DeMaio, A., Mehrotra, S., Sambamurti, K., Husain, S., 2022. the role of the adaptive
immune system and T cell dysfunction in neurodegenerative diseases. Journal of
Neuroinflammation 19 (1), 251. https://doi.org/10.1186/s12974-022-02605-9.
De-Paula, V.J., Radanovic, M., Diniz, B.S., Forlenza, O.V., 2012. Alzheimer’s disease.
SubcellBiochem. 65, 329–352. https://doi.org/10.1007/978-94-007-5416-4_14.
DeTure, M.A., Dickson, D.W., 2019. The neuropathological diagnosis of alzheimer’s
disease. MolNeurodegener. 14 (1), 32. https://doi.org/10.1186/s13024-019-0333-5.
Dionisio-Santos, D.A., Olschowka, J.A., O’Banion, M.K., 2019. Exploiting microglial and
peripheral immune cell crosstalk to treat alzheimer’s disease. Journal of
Neuroinflammation 16, 74. https://doi.org/10.1186/s12974-019-1453-0.
Dong, Y., Benveniste, E.N., 2001. Immune function of astrocytes. Glia 36 (2), 180–190.
https://doi.org/10.1002/glia.1107.
Dong, X., Nao, J., Shi, J., Zheng, D., 2019. Predictive value of routine peripheral blood
biomarkers in alzheimer’s disease. Frontiers in Aging Neuroscience 5 (11), 332.
https://doi.org/10.3389/fnagi.2019.00332.
Dorszewska, J., Prendecki, M., Oczkowska, A., Dezor, M., Kozubski, W., 2016. Molecular
basis of familial and sporadic alzheimer’s disease. Current Alzheimer Research 13
(9), 952–963. https://doi.org/10.2174/1567205013666160314150501. PMID:
26971934.
Dubois, B., Hampel, H., Feldman, H.H., Scheltens, P., Aisen, P., Andrieu, S.,
Bakardjian, H., Benali, H., Bertram, L., Blennow, K., Broich, K., Cavedo, E.,
Crutch, S., Dartigues, J.-F., Duyckaerts, C., Epelbaum, S., Frisoni, G.B., Gauthier, S.,
Genthon, R., Gouw, A.A., Habert, M.-O., Holtzman, D.M., Kivipelto, M., Lista, S.,
Molinuevo, J.-L., O’Bryant, S.E., Rabinovici, G.D., Rowe, C., Salloway, S.,
Schneider, L.S., Sperling, R., Teichmann, M., Carrillo, M.C., Cummings, J., Jack, C.
R., 2016. Preclinical alzheimer’s disease: Definition, natural history, and diagnostic
criteria. alzheimer’s & Dementia 12 (3), 292–323.
Duffy, S.S., Keating, B.A., Perera, C.J., Moalem-Taylor, G., 2018. The role of regulatory T
cells in nervous system pathologies. Journal of Neuroscience Research 96 (6),
951–968. https://doi.org/10.1002/jnr.24073.
Dutra, R.C., Moreira, E.L.G., Alberti, T.B., Marcon, R., Prediger, R.D., Calixto, J.B., 2013.
Spatial reference memory deficits precede motor dysfunction in an experimental
autoimmune encephalomyelitis model: the role of kallikrein-kinin system. Brain,
Behavior, and Immunity 33, 90–101. https://doi.org/10.1016/j.bbi.2013.06.002.
Edwards, F.A., 2019. A unifying hypothesis for alzheimer’s disease: from plaques to
neurodegeneration. Trends in Neurosciences 42 (5), 310–322. https://doi.org/
10.1016/j.tins.2019.03.003.
El Khoury, J., Toft, M., Hickman, S.E., Means, T.K., Terada, K., Geula, C., Luster, A.D.,
2007. Ccr2 deficiency impairs microglial accumulation and accelerates progression
of alzheimer-like disease. Nature Medicine 13 (4), 432–438. https://doi.org/
10.1038/nm1555.
Engelhardt, B., Vajkoczy, P., Weller, R.O., 2017. the movers and shapers in immune
privilege of the CNS. Nature Immunology 18 (2), 123–131. https://doi.org/10.1038/
ni.3666.
Erickson, M.A., Banks, W.A., 2013. Blood-brain barrier dysfunction as a cause and
consequence of alzheimer’s disease. Journal of Cerebral Blood Flow and Metabolism
33 (10), 1500–1513. https://doi.org/10.1038/jcbfm.2013.135.
Erickson, M.A., Morofuji, Y., Owen, J.B., Banks, W.A., 2014. Rapid transport of CCL11
across the blood-brain barrier: regional variation and importance of blood cells. The
Journal of Pharmacology and Experimental Therapeutics 349 (3), 497–507. https://
doi.org/10.1124/jpet.114.213074.
Fan, Z., Brooks, D.J., Okello, A., Edison, P., 2017. An early and late peak in microglial
activation in alzheimer’s disease trajectory. Brain 140 (3), 792–803. https://doi.org/
10.1093/brain/aww349. PMID: 28122877; PMCID: PMC5837520.
Fani, L., Georgakis, M.K., Ikram, M.A., Ikram, M.K., Malik, R., Dichgans, M., 2021.
Circulating biomarkers of immunity and inflammation, risk of alzheimer’s disease,
and hippocampal volume: a mendelian randomization study. Translational
Psychiatry 11 (1), 291. https://doi.org/10.1038/s41398-021-01400-z.
Ferretti, M.T., Merlini, M., Späni, C., Gericke, C., Schweizer, N., Enzmann, G.,
Engelhardt, B., Kulic, L., Suter, T., Nitsch, R.M., 2016. T-cell brain infiltration and
immature antigen-presenting cells in transgenic models of alzheimer’s disease-like
cerebral amyloidosis. Brain, Behavior, and Immunity 54, 211–225. https://doi.org/
10.1016/j.bbi.2016.02.009.
Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC,
Gustavson A, Sayre J, Sofroni E, Suarez T, Chiappelli F, Bernard G. Ineffective
phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J
Alzheimers Dis. 2005 Jun;7(3):221-32; discussion 255-62. doi: 10.3233/jad-2005-
7304.
Fisher Y, Strominger I, Biton S, Nemirovsky A, Baron R, Monsonego A. Th1 polarization
of T cells injected into the cerebrospinal fluid induces brain immunosurveillance. J
Immunol. 2014 Jan 1;192(1):92-102. doi: 10.4049/jimmunol.1301707.
Frackowiak, J., Wisniewski, H.M., Wegiel, J., Merz, G.S., Iqbal, K., Wang, K.C., 1992.
Ultrastructure of the microglia that phagocytose amyloid and the microglia that
produce beta-amyloid fibrils. Acta Neuropathologica 84 (3), 225–233. https://doi.
org/10.1007/BF00227813.
Fransen, N.L., Hsiao, C.C., van der Poel, M., Engelenburg, H.J., Verdaasdonk, K.,
Vincenten, M.C.J., Remmerswaal, E.B.M., Kuhlmann, T., Mason, M.R.J., Hamann, J.,
11
Brain Research 1821 (2023) 148589
Smolders, J., Huitinga, I., 2020. Tissue-resident memory T cells invade the brain
parenchyma in multiple sclerosis white matter lesions. Brain 143 (6), 1714–1730.
https://doi.org/10.1093/brain/awaa117.
Garbuz DG, Zatsepina OG, Evgen’ev MB. [Beta Amyloid, Tau Protein, and
Neuroinflammation: An Attempt to Integrate Different Hypotheses of Alzheimer’s
Disease Pathogenesis]. Mol Biol (Mosk). 2021 Sep-Oct;55(5):734-747. Russian. doi:
10.31857/S0026898421050049. PMID: 34671002.
Gate, D., Saligrama, N., Leventhal, O., Yang, A.C., Unger, M.S., Middeldorp, J., Chen, K.,
Lehallier, B., Channappa, D., De Los Santos, M.B., McBride, A., Pluvinage, J.,
Elahi, F., Tam, G.K., Kim, Y., Greicius, M., Wagner, A.D., Aigner, L., Galasko, D.R.,
Davis, M.M., Wyss-Coray, T., 2020. Clonally expanded CD8 T cells patrol the
cerebrospinal fluid in alzheimer’s disease. Nature 577 (7790), 399–404. https://doi.
org/10.1038/s41586-019-1895-7.
Gatz, M., Reynolds, C.A., Fratiglioni, L., Johansson, B., Mortimer, J.A., Berg, S., Fiske, A.,
Pedersen, N.L., 2006. Role of genes and environments for explaining alzheimer
disease. Archives of General Psychiatry 63 (2), 168–174. https://doi.org/10.1001/
archpsyc.63.2.168. PMID: 16461860.
Gendelman, H.E., Mosley, R.L., 2015. A perspective on roles played by innate and
adaptive immunity in the pathobiology of neurodegenerative disorders. Journal of
Neuroimmune Pharmacology 10 (4), 645–650. https://doi.org/10.1007/s11481-
015-9639-4.
Goverman, J., 2009. Autoimmune T cell responses in the central nervous system. Nature
Reviews. Immunology 9 (6), 393–407. https://doi.org/10.1038/nri2550.
Guerreiro, R., Bras, J., 2015. The age factor in alzheimer’s disease. Genome Medicine 20
(7), 106. https://doi.org/10.1186/s13073-015-0232-5.
Hamelin, L., Lagarde, J., Dorothée, G., Leroy, C., Labit, M., Comley, R.A., de Souza, L.C.,
Corne, H., Dauphinot, L., Bertoux, M., Dubois, B., Gervais, P., Colliot, O., Potier, M.
C., Bottlaender, M., Sarazin, M., 2016. Early and protective microglial activation in
alzheimer’s disease: a prospective study using 18 F-DPA-714 PET imaging. Brain 139
(4), 1252–1264.
Harry, G.J., 2013. Microglia during development and aging. Pharmacology &
Therapeutics 139 (3), 313–326. https://doi.org/10.1016/j.
pharmthera.2013.04.013.
Heneka, M.T., O’Banion, M.K., Terwel, D., Kummer, M.P., 2010. Neuroinflammatory
processes in alzheimer’s disease. Journal of Neural Transmission (Vienna) 117 (8),
919–947. https://doi.org/10.1007/s00702-010-0438-z.
Heneka, M.T., Carson, M.J., Khoury, J.E., Landreth, G.E., Brosseron, F., Feinstein, D.L.,
Jacobs, A.H., Wyss-Coray, T., Vitorica, J., Ransohoff, R.M., Herrup, K., Frautschy, S.
A., Finsen, B., Brown, G.C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E.,
Halle, A., Petzold, G.C., Town, T., Morgan, D., Shinohara, M.L., Perry, V.H.,
Holmes, C., Bazan, N.G., Brooks, D.J., Hunot, S., Joseph, B., Deigendesch, N.,
Garaschuk, O., Boddeke, E., Dinarello, C.A., Breitner, J.C., Cole, G.M., Golenbock, D.
T., Kummer, M.P., 2015. Neuroinflammation in alzheimer’s disease. Lancet
Neurology 14 (4), 388–405.
Herrera CA, Prince M, Knapp M, Karagiannidou M, and Guerchet M.World Alzheimer
Report 2016: Improving healthcare for people living with dementia. Coverage,
quality and costs now and in the future. 2016 Sep. doi:10.13140/
RG.2.2.22580.04483.
Hickman, S., Izzy, S., Sen, P., Morsett, L., El Khoury, J., 2018. Microglia in
neurodegeneration. Nature Neuroscience 21 (10), 1359–1369. https://doi.org/
10.1038/s41593-018-0242-x.
Höftberger, R., Aboul-Enein, F., Brueck, W., Lucchinetti, C., Rodriguez, M.,
Schmidbauer, M., Jellinger, K., Lassmann, H., 2004. Expression of major
histocompatibility complex class I molecules on the different cell types in multiple
sclerosis lesions. Brain Pathology 14 (1), 43–50. https://doi.org/10.1111/j.1750-
3639.2004.tb00496.x.
Hopperton, K.E., Mohammad, D., Trépanier, M.O., Giuliano, V., Bazinet, R.P., 2018.
Markers of microglia in post-mortem brain samples from patients with alzheimer’s
disease: a systematic review. Molecular Psychiatry 23 (2), 177–198.
Iqbal, K., Liu, F., Gong, C.X., Alonso Adel, C., Grundke-Iqbal, I., 2009. Mechanisms of
tau-induced neurodegeneration. Acta Neuropathologica 118 (1), 53–69. https://doi.
org/10.1007/s00401-009-0486-3.
Ismail, R., Parbo, P., Madsen, L.S., Hansen, A.K., Hansen, K.V., Schaldemose, J.L.,
Kjeldsen, P.L., Stokholm, M.G., Gottrup, H., Eskildsen, S.F., Brooks, D.J., 2020. The
relationships between neuroinflammation, beta-amyloid and tau deposition in
alzheimer’s disease: a longitudinal PET study. Journal of Neuroinflammation 17 (1),
151. https://doi.org/10.1186/s12974-020-01820-6. PMID: 32375809; PMCID:
PMC7203856.
Ittner, L.M., Götz, J., 2011. Amyloid-β and tau–a toxic pas de deux in alzheimer’s disease.
Nature Reviews. Neuroscience 12 (2), 65–72. https://doi.org/10.1038/nrn2967.
Ittner, L.M., Ke, Y.D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., Wölfing, H.,
Chieng, B.C., Christie, M.J., Napier, I.A., Eckert, A., Staufenbiel, M., Hardeman, E.,
Götz, J., 2010. Dendritic function of tau mediates amyloid-beta toxicity in
alzheimer’s disease mouse models. Cell 142 (3), 387–397. https://doi.org/10.1016/
j.cell.2010.06.036.
Iturria-Medina, Y., Sotero, R.C., Toussaint, P.J., Mateos-Pérez, J.M., Evans, A.C.,
Weiner, M.W., Aisen, P., Petersen, R., Jack, C.R., Jagust, W., Trojanowki, J.Q.,
Toga, A.W., Beckett, L., Green, R.C., Saykin, A.J., Morris, J., Shaw, L.M.,
Khachaturian, Z., Sorensen, G., Kuller, L., Raichle, M., Paul, S., Davies, P., Fillit, H.,
Hefti, F., Holtzman, D., Mesulam, M.M., Potter, W., Snyder, P., Schwartz, A.,
Montine, T., Thomas, R.G., Donohue, M., Walter, S., Gessert, D., Sather, T.,
Jiminez, G., Harvey, D., Bernstein, M., Fox, N., Thompson, P., Schuff, N.,
Borowski, B., Gunter, J., Senjem, M., Vemuri, P., Jones, D., Kantarci, K., Ward, C.,
Koeppe, R.A., Foster, N., Reiman, E.M., Chen, K., Mathis, C., Landau, S., Cairns, N.J.,
Householder, E., Taylor-Reinwald, L., Lee, V., Korecka, M., Figurski, M.,
Crawford, K., Neu, S., Foroud, T.M., Potkin, S., Shen, L.i., Faber, K., Kim, S., Nho, K.,
M.O. Asamu et al.
Thal, L., Buckholtz, N., Albert, M., Frank, R., Hsiao, J., Kaye, J., Quinn, J., Lind, B.,
Carter, R., Dolen, S., Schneider, L.S., Pawluczyk, S., Beccera, M., Teodoro, L.,
Spann, B.M., Brewer, J., Vanderswag, H., Fleisher, A., Heidebrink, J.L., Lord, J.L.,
Mason, S.S., Albers, C.S., Knopman, D., Johnson, K., Doody, R.S., Villanueva-
Meyer, J., Chowdhury, M., Rountree, S., Dang, M., Stern, Y., Honig, L.S., Bell, K.L.,
Ances, B., Carroll, M., Leon, S., Mintun, M.A., Schneider, S., Oliver, A., Marson, D.,
Griffith, R., Clark, D., Geldmacher, D., Brockington, J., Roberson, E., Grossman, H.,
Mitsis, E., de Toledo-Morrell, L., Shah, R.C., Duara, R., Varon, D., Greig, M.T.,
Roberts, P., Albert, M., Onyike, C., D’Agostino, D., Kielb, S., Galvin, J.E.,
Cerbone, B., Michel, C.A., Rusinek, H., de Leon, M.J., Glodzik, L., De Santi, S.,
Doraiswamy, P.M., Petrella, J.R., Wong, T.Z., Arnold, S.E., Karlawish, J.H., Wolk, D.,
Smith, C.D., Jicha, G., Hardy, P., Sinha, P., Oates, E., Conrad, G., Lopez, O.L.,
Oakley, MaryAnn, Simpson, D.M., Porsteinsson, A.P., Goldstein, B.S., Martin, K.,
Makino, K.M., Ismail, M.S., Brand, C., Mulnard, R.A., Thai, G., Mc-Adams-Ortiz, C.,
Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Weiner, M.,
Martin-Cook, K., DeVous, M., Levey, A.I., Lah, J.J., Cellar, J.S., Burns, J.M.,
Anderson, H.S., Swerdlow, R.H., Apostolova, L., Tingus, K., Woo, E., Silverman, D.H.
S., Lu, P.H., Bartzokis, G., Graff-Radford, N.R., Parfitt, F., Kendall, T., Johnson, H.,
Farlow, M.R., Hake, AnnMarie, Matthews, B.R., Herring, S., Hunt, C., van Dyck, C.H.,
Carson, R.E., MacAvoy, M.G., Chertkow, H., Bergman, H., Hosein, C., Black, S.,
Stefanovic, B., Caldwell, C., Hsiung, G.-Y., Feldman, H., Mudge, B., Assaly, M.,
Kertesz, A., Rogers, J., Bernick, C., Munic, D., Kerwin, D., Mesulam, M.-M.,
Lipowski, K., Wu, C.-K., Johnson, N., Sadowsky, C., Martinez, W., Villena, T.,
Turner, R.S., Johnson, K., Reynolds, B., Sperling, R.A., Johnson, K.A., Marshall, G.,
Frey, M., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M.N., Belden, C.M.,
Jacobson, S.A., Sirrel, S.A., Kowall, N., Killiany, R., Budson, A.E., Norbash, A.,
Johnson, P.L., Allard, J., Lerner, A., Ogrocki, P., Hudson, L., Fletcher, E.,
Carmichael, O., Olichney, J., DeCarli, C., Kittur, S., Borrie, M., Lee, T.-Y., Bartha, R.,
Johnson, S., Asthana, S., Carlsson, C.M., Potkin, S.G., Preda, A., Nguyen, D.,
Tariot, P., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, D.W., Kataki, M.,
Adeli, A., Zimmerman, E.A., Celmins, D., Brown, A.D., Pearlson, G.D., Blank, K.,
Anderson, K., Santulli, R.B., Kitzmiller, T.J., Schwartz, E.S., Sink, K.M.,
Williamson, J.D., Garg, P., Watkins, F., Ott, B.R., Querfurth, H., Tremont, G.,
Salloway, S., Malloy, P., Correia, S., Rosen, H.J., Miller, B.L., Mintzer, J., Spicer, K.,
Bachman, D., Finger, E., Pasternak, S., Rachinsky, I., Drost, D., Pomara, N.,
Hernando, R., Sarrael, A., Schultz, S.K., Ponto, L.L.B., Shim, H., Smith, K.E.,
Relkin, N., Chaing, G., Raudin, L., Smith, A., Fargher, K., Raj, B.A., Neylan, T.,
Grafman, J., Davis, M., Morrison, R., Hayes, J., Finley, S., Friedl, K., Fleischman, D.,
Arfanakis, K., James, O., Massoglia, D., Fruehling, J.J., Harding, S., Peskind, E.R.,
Petrie, E.C., Li, G., Yesavage, J.A., Taylor, J.L., Furst, A.J., 2016. Alzheimer’s disease
neuroimaging initiative. Early role of vascular dysregulation on late-onset
alzheimer’s disease based on multifactorial data-driven analysis. Nature
Communications 7 (1). https://doi.org/10.1038/ncomms11934.
Jahn, H., 2013. Memory loss in alzheimer’s disease. Dialogues ClinNeurosci. 15 (4),
445–454. https://doi.org/10.31887/DCNS.2013.15.4/hjahn.
Janelidze, S., Mattsson, N., Stomrud, E., Lindberg, O., Palmqvist, S., Zetterberg, H.,
Blennow, K., Hansson, O., 2018. CSF biomarkers of neuroinflammation and
cerebrovascular dysfunction in early alzheimer disease. Neurology 91 (9),
e867–e877.
Ji, K., Akgul, G., Wollmuth, L.P., Tsirka, S.E., Dunaevsky, A., 2013. Microglia actively
regulate the number of functional synapses. PLoS One1 8 (2), e56293.
Kawakami, N.; Lassmann, S.; Li, Z.; Odoardi, F.; Ritter, T.; Ziemssen, T.; Klinkert, W.E.F.;
Ellwart, J.W.; Bradl, M.; Krivacic, K.; et al. The Activation Status of Neuroantigen-
Specific T Cells in the Target Organ Determines the Clinical Outcome of
Autoimmune Encephalomyelitis. J. Exp. Med. 2004, 199, 185–197. doi: https://doi.
org/10.1084/jem.20031064.
Kebir, H., Kreymborg, K., Ifergan, I., Dodelet-Devillers, A., Cayrol, R., Bernard, M.,
Giuliani, F., Arbour, N., Becher, B., Prat, A., 2007. Human TH17 lymphocytes
promote blood-brain barrier disruption and central nervous system inflammation.
Nature Medicine 13 (10), 1173–1175. https://doi.org/10.1038/nm1651.
Kelly, R.J., Minogue, A.M., Lyons, A., Jones, R.S., Browne, T.C., Costello, D.A.,
Denieffe, S., O’Sullivan, C., Connor, T.J., Lynch, M.A., 2013. Glial activation in
AβPP/PS1 mice is associated with infiltration of IFNγ-Producing cells. Journal of
Alzheimer’s Disease 37 (1), 63–75. https://doi.org/10.3233/JAD-130539.
Kessler B, Hudrisier D, Schroeter M, Tschopp J, Cerottini JC, Luescher IF. Peptide
modification or blocking of CD8, resulting in weak TCR signaling, can activate CTL
for Fas- but not perforin-dependent cytotoxicity or cytokine production. J Immunol.
(1998) 161:6939–46.
Kierdorf, K., Prinz, M., 2013. Factors regulating microglia activation. Frontiers in
Cellular Neuroscience 23 (7), 44. https://doi.org/10.3389/fncel.2013.00044.
Kivisäkk, P., Tucky, B., Wei, T., Campbell, J.J., Ransohoff, R.M., 2006. Human
cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific
trafficking determinants: relevance for immunotherapy. BMC Immunology 7 (7), 14.
https://doi.org/10.1186/1471-2172-7-14.
Knezevic, D., Verhoeff, N.P.LG., Hafizi, S., Strafella, A.P., Graff-Guerrero, A., Rajji, T.,
Pollock, B.G., Houle, S., Rusjan, P.M., Mizrahi, R., 2018. Imaging microglial
activation and amyloid burden in amnestic mild cognitive impairment. Journal of
Cerebral Blood Flow and Metabolism 38 (11), 1885–1895.
Koch, G., Di Lorenzo, F., Del Olmo, M.F., Bonní, S., Ponzo, V., Caltagirone, C.,
Bozzali, M., Martorana, A., 2016. Reversal of LTP-Like cortical plasticity in
alzheimer’s disease patients with Tau-Related faster clinical progression. Journal of
Alzheimer’s Disease 50 (2), 605–616. https://doi.org/10.3233/JAD-150813.
Konjevic Sabolek, M., Held, K., Beltrán, E., Niedl, A.G., Meinl, E., Hohlfeld, R.,
Lassmann, H., Dornmair, K., 2019. Communication of CD8+ T cells with
mononuclear phagocytes in multiple sclerosis. Annals of Clinical Translational
Neurology 6 (7), 1151–1164. https://doi.org/10.1002/acn3.783.
12
Brain Research 1821 (2023) 148589
Korin, B., Ben-Shaanan, T.L., Schiller, M., Dubovik, T., Azulay-Debby, H., Boshnak, N.T.,
Koren, T., Rolls, A., 2017. High-dimensional, single-cell characterization of the
brain’s immune compartment. Nature Neuroscience 20 (9), 1300–1309. https://doi.
org/10.1038/nn.4610.
Kovac A, Zilka N, Kazmerova Z, Cente M, Zilkova M, Novak M. Misfolded truncated
protein τ induces innate immune response via MAPK pathway. J Immunol. 2011 Sep
1;187(5):2732-9. doi: 10.4049/jimmunol.1100216. Epub 2011 Aug 3. PMID:
21813771.
Krishnan, A., Kocab, A.J., Zacks, D.N., Marshak-Rothstein, A., GregoryKsander, M., 2019.
A small peptide antagonist of the fas receptor inhibits neuroinflammation and
prevents axon degeneration and retinal ganglion cell death in an inducible mouse
model of glaucoma. Journal of Neuroinflammation 16, 184. https://doi.org/
10.1186/s12974-019-1576-3.
Kumar, P., Pradhan, K., Karunya, R., Ambasta, R.K., Querfurth, H.W., 2012. Cross-
functional E3 ligases parkin and c-terminus Hsp70-interacting protein in
neurodegenerative disorders. Journal of Neurochemistry 120 (3), 350–370. https://
doi.org/10.1111/j.1471-4159.2011.07588.x.
Kuyumcu, M.E., Yesil, Y., Oztürk, Z.A., Kizilarslanoğlu, C., Etgül, S., Halil, M., Ulger, Z.,
Cankurtaran, M., Arıoğul, S., 2012. The evaluation of neutrophil-lymphocyte ratio in
alzheimer’s disease. Dementia and Geriatric Cognitive Disorders 34 (2), 69–74.
https://doi.org/10.1159/000341583.
Lassmann, H., 2018. Multiple sclerosis pathology. Cold Spring Harbor Perspectives in
Medicine 8 (3), a028936.
Laurent, C., Dorothée, G., Hunot, S., Martin, E., Monnet, Y., Duchamp, M., Dong, Y.,
Légeron, F.P., Leboucher, A., Burnouf, S., Faivre, E., Carvalho, K., Caillierez, R.,
Zommer, N., Demeyer, D., Jouy, N., Sazdovitch, V., Schraen-Maschke, S.,
Delarasse, C., Buée, L., Blum, D., 2017. Hippocampal T cell infiltration promotes
neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain 140
(1), 184–200. https://doi.org/10.1093/brain/aww270.
Laurent, C., Buée, L., Blum, D., 2018. Tau and neuroinflammation: What impact for
alzheimer’s disease and tauopathies? Biomed J. 41 (1), 21–33. https://doi.org/
10.1016/j.bj.2018.01.003.
Leng, F., Hinz, R., Gentleman, S., Hampshire, A., Dani, M., Brooks, D.J., Edison, P., 2023.
Neuroinflammation is independently associated with brain network dysfunction in
alzheimer’s disease. Molecular Psychiatry 28 (3), 1303–1311.
Li, M., Shang, D.S., Zhao, W.D., Tian, L., Li, B., Fang, W.G., Zhu, L., Man, S.M., Chen, Y.
H., 2009. Amyloid beta interaction with receptor for advanced glycation end
products up-regulates brain endothelial CCR5 expression and promotes T cells
crossing the blood-brain barrier. Journal of Immunology 182 (9), 5778–5788.
https://doi.org/10.4049/jimmunol.0803013.
Liu, R., Wang, J.Z., 2009. Protein phosphatase 2A in alzheimer’s disease.
Pathophysiology 16 (4), 273–277. https://doi.org/10.1016/j.
pathophys.2009.02.008.
Lowther, D.E., Hafler, D.A., 2012. Regulatory T cells in the central nervous system.
Immunology Reviews 248 (1), 156–169. https://doi.org/10.1111/j.1600-
065X.2012.01130.x.
Lue, L.F., Rydel, R., Brigham, E.F., Yang, L.B., Hampel, H., Murphy Jr, G.M.,
Brachova, L., Yan, S.D., Walker, D.G., Shen, Y., Rogers, J., 2001. inflammatory
repertoire of alzheimer’s disease and nondemented elderly microglia in vitro. Glia 35
(1), 72–79. https://doi.org/10.1002/glia.1072. PMID: 11424194.
Lueg, G., Gross, C.C., Lohmann, H., Johnen, A., Kemmling, A., Deppe, M., Groger, J.,
Minnerup, J., Wiendl, H., Meuth, S.G., Duning, T., 2015. Clinical relevance of
specific t-cell activation in the blood and cerebrospinal fluid of patients with mild
alzheimer’s disease. Neurobiology of Aging 36 (1), 81–89. https://doi.org/10.1016/
j.neurobiolaging.2014.08.008.
Ma X, Reynolds SL, Baker BJ, Li X, Benveniste EN, Qin H. IL-17 enhancement of the IL-6
signaling cascade in astrocytes. J Immunol. 2010 May 1;184(9):4898-906. doi:
10.4049/jimmunol.1000142.
Machado-Santos, J., Saji, E., Tröscher, A.R., Paunovic, M., Liblau, R., Gabriely, G.,
Bien, C.G., Bauer, J., Lassmann, H., 2018. the compartmentalized inflammatory
response in the multiple sclerosis brain is composed of tissue-resident CD8+ T
lymphocytes and B cells. Brain 141 (7), 2066–2082. https://doi.org/10.1093/brain/
awy151.
Machhi, J., Sinha, A., Patel, P., Kanhed, A.M., Upadhyay, P., Tripathi, A., Parikh, Z.S.,
Chruvattil, R., Pillai, P.P., Gupta, S., Patel, K., Giridhar, R., Yadav, M.R., 2016.
Neuroprotective potential of novel Multi-Targeted isoalloxazine derivatives in
rodent models of alzheimer’s disease through activation of canonical wnt/β-Catenin
signalling pathway. Neurotoxicity Research 29 (4), 495–513. https://doi.org/
10.1007/s12640-016-9598-4. Epub 2016 Jan 21.
Machhi, J., Prajapati, N., Tripathi, A., Parikh, Z.S., Kanhed, A.M., Patel, K., Pillai, P.P.,
Giridhar, R., Yadav, M.R., 2017. Synthesis and biological evaluation of novel Multi-
target-Directed benzazepines against excitotoxicity. MolNeurobiol. 54 (9),
6697–6722. https://doi.org/10.1007/s12035-016-0184-9.
Machhi, J., Kevadiya, B.D., Muhammad, I.K., Herskovitz, J., Olson, K.E., Mosley, R.L.,
Gendelman, H.E., 2020. Harnessing regulatory T cell neuroprotective activities for
treatment of neurodegenerative disorders. Molecular Neurodegeneration 15 (1), 32.
https://doi.org/10.1186/s13024-020-00375-7.
Machhi, J., Yeapuri, P., Lu, Y., Foster, E., Chikhale, R., Herskovitz, J., Namminga, K.L.,
Olson, K.E., Abdelmoaty, M.M., Gao, J., Quadros, R.M., Kiyota, T., Jingjing, L.,
Kevadiya, B.D., Wang, X., Liu, Y., Poluektova, L.Y., Gurumurthy, C.B., Mosley, R.L.,
Gendelman, H.E., 2021. CD4+ effector T cells accelerate alzheimer’s disease in mice.
Journal of Neuroinflammation 18 (1), 272. https://doi.org/10.1186/s12974-021-
02308-7.
Malm, T.M., Koistinaho, M., Pärepalo, M., Vatanen, T., Ooka, A., Karlsson, S.,
Koistinaho, J., 2005. Bone-marrow-derived cells contribute to the recruitment of
microglial cells in response to beta-amyloid deposition in APP/PS1 double
M.O. Asamu et al.
transgenic alzheimer mice. Neurobiology of Disease 18 (1), 134–142. https://doi.
org/10.1016/j.nbd.2004.09.009.
Malm, T., Koistinaho, M., Muona, A., Magga, J., Koistinaho, J., 2010. The role and
therapeutic potential of monocytic cells in alzheimer’s disease. Glia 58 (8), 889–900.
https://doi.org/10.1002/glia.20973.
Marco, S., Skaper, S.D., 2006. Amyloid beta-peptide1-42 alters tight junction protein
distribution and expression in brain microvessel endothelial cells. NeurosciLett. 401
(3), 219–224. https://doi.org/10.1016/j.neulet.2006.03.047.
Masters, C.L., Selkoe, D.J., 2012. Biochemistry of amyloid β-protein and amyloid deposits
in alzheimer disease. Cold Spring HarbPerspect Med. 2 (6), a006262 https://doi.org/
10.1101/cshperspect.a006262.
Mathys, H., Adaikkan, C., Gao, F., Young, J.Z., Manet, E., Hemberg, M., De Jager, P.L.,
Ransohoff, R.M., Regev, A., Tsai, L.H., 2017. Temporal tracking of microglia
activation in neurodegeneration at Single-Cell resolution. Cell Reports 21 (2),
366–380. https://doi.org/10.1016/j.celrep.2017.09.039.
Mattson, M.P., 2002. Oxidative stress, perturbed calcium homeostasis, and immune
dysfunction in alzheimer’s disease. Journal of Neurovirology 8 (6), 539–550.
https://doi.org/10.1080/13550280290100978.
McGeer, P.L., McGeer, E.G., 2013. The amyloid cascade-inflammatory hypothesis of
alzheimer disease: implications for therapy. Acta Neuropathologica 126 (4),
479–497. https://doi.org/10.1007/s00401-013-1177-7.
Medana, I.M., Gallimore, A., Oxenius, A., Martinic, M.M., Wekerle, H., Neumann, H.,
2000. MHC class i-restricted killing of neurons by virusspecific CD8+ T lymphocytes
is effected through the Fas/FasL, but not the perforin pathway. European Journal of
Immunology 30, 3623–3633. https://doi.org/10.1002/1521-4141(200012)30:
12<3623::AID-IMMU3623>3.0.CO;2-F.
Medeiros, R., Baglietto-Vargas, D., LaFerla, F.M., 2011. The role of tau in alzheimer’s
disease and related disorders. CNS NeurosciTher. 17 (5), 514–524. https://doi.org/
10.1111/j.1755-5949.2010.00177.x.
Melzer, N., Meuth, S.G., Wiendl, H., 2009. CD8+ T cells and neuronal damage: direct and
collateral mechanisms of cytotoxicity and impaired electrical excitability. The
FASEB Journal 23, 3659–3673. https://doi.org/10.1096/fj.09-136200.
Mendez, M.F., 2019. Early-onset alzheimer disease and its variants. Continuum
(MinneapMinn). 25 (1), 34–51. https://doi.org/10.1212/CON.0000000000000687.
Merlini, M., Kirabali, T., Kulic, L., Nitsch, R.M., Ferretti, M.T., 2018. Extravascular CD3+
T cells in brains of alzheimer disease patients correlate with tau but not with amyloid
pathology: an immunohistochemical study. Neuro-Degenerative Diseases 18 (1),
49–56. https://doi.org/10.1159/000486200.
Meuth, S.G., Herrmann, A.M., Simon, O.J., Siffrin, V., Melzer, N., Bittner, S., Meuth, P.,
Langer, H.F., Hallermann, S., Boldakowa, N., Herz, J., Munsch, T., Landgraf, P.,
Aktas, O., Heckmann, M., Lessmann, V., Budde, T., Kieseier, B.C., Zipp, F.,
Wiendl, H., 2009. Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent
electrical silencing precedes but is not causally linked to neuronal cell death. The
Journal of Neuroscience 29 (49), 15397–15409. https://doi.org/10.1523/
JNEUROSCI.4339-09.2009.
Michaud, J.P., Bellavance, M.A., Préfontaine, P., Rivest, S., 2013. Real-time in vivo
imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Reports
5 (3), 646–653. https://doi.org/10.1016/j.celrep.2013.10.010.
Mietelska-Porowska, A., Wojda, U., 2017. T lymphocytes and inflammatory mediators in
the interplay between brain and blood in alzheimer’s disease: Potential pools of new
biomarkers. Journal of Immunology Research 2017, 4626540. https://doi.org/
10.1155/2017/4626540.
Mittal, K., Eremenko, E., Berner, O., Elyahu, Y., Strominger, I., Apelblat, D.,
Nemirovsky, A., Spiegel, I., Monsonego, A., 2019. CD4 T Cells Induce A Subset of
MHCII-Expressing Microglia that Attenuates Alzheimer Pathology. iScience. 28 (16),
298–311. https://doi.org/10.1016/j.isci.2019.05.039.
Mokhtar SH, Bakhuraysah MM, Cram DS, Petratos S. The Beta-amyloid protein of
Alzheimer’s disease: communication breakdown by modifying the neuronal
cytoskeleton. Int J Alzheimers Dis. 2013;2013:910502. doi: 10.1155/2013/910502.
Mondragón-Rodríguez, S., Salgado-Burgos, H., Peña-Ortega, F., 2020. Circuitry and
synaptic dysfunction in alzheimer’s disease: A new tau hypothesis. Neural Plasticity
1 (2020), 2960343. https://doi.org/10.1155/2020/2960343.
Montagne, A., Barnes, S.R., Sweeney, M.D., Halliday, M.R., Sagare, A.P., Zhao, Z.,
Toga, A.W., Jacobs, R.E., Liu, C.Y., Amezcua, L., Harrington, M.G., Chui, H.C.,
Law, M., Zlokovic, B.V., 2015. Blood-brain barrier breakdown in the aging human
hippocampus. Neuron 85 (2), 296–302. https://doi.org/10.1016/j.
neuron.2014.12.032.
Monteiro, S., Ferreira, F.M., Pinto, V., Roque, S., Morais, M., de Sá-Calçada, D., Mota, C.,
Correia-Neves, M., Cerqueira, J.J., 2016. Absence of IFNγ promotes hippocampal
plasticity and enhances cognitive performance. Translational Psychiatry 6 (1), e707.
Morales, I., Jiménez, J.M., Mancilla, M., Maccioni, R.B., 2013. Tau oligomers and fibrils
induce activation of microglial cells. Journal of Alzheimer’s Disease 37 (4), 849–856.
https://doi.org/10.3233/JAD-131843.
Morris, G., Berk, M., Maes, M., Puri, B.K., 2019. Could alzheimer’s disease originate in
the periphery and if so how so? Molecular Neurobiology 56 (1), 406–434. https://
doi.org/10.1007/s12035-018-1092-y.
Mount, M.P., Lira, A., Grimes, D., Smith, P.D., Faucher, S., Slack, R., Anisman, H.,
Hayley, S., Park, D.S., 2007. involvement of interferon-gamma in microglial-
mediated loss of dopaminergic neurons. The Journal of Neuroscience 27 (12),
3328–3337. https://doi.org/10.1523/JNEUROSCI.5321-06.2007.
Mundt, S., Mrdjen, D., Utz, S.G., Greter, M., Schreiner, B., Becher, B., 2019. Conventional
DCs sample and present myelin antigens in the healthy CNS and allow parenchymal
T cell entry to initiate neuroinflammation. Science Immunology. https://doi.org/
10.1126/sciimmunol.aau8380. Jan 25;4(31):eaau8380.
13
Brain Research 1821 (2023) 148589
Murphy, M.P., LeVine 3rd., H., 2010. Alzheimer’s disease and the amyloid-beta peptide.
Journal of Alzheimer’s Disease 19 (1), 311–323. https://doi.org/10.3233/JAD-
2010-1221.
Naert, G., Rivest, S., 2011. CC chemokine receptor 2 deficiency aggravates cognitive
impairments and amyloid pathology in a transgenic mouse model of alzheimer’s
disease. The Journal of Neuroscience 31 (16), 6208–6220. https://doi.org/10.1523/
JNEUROSCI.0299-11.2011.
Nazem, A., Mansoori, G.A., 2008. Nanotechnology solutions for alzheimer’s disease:
advances in research tools, diagnostic methods and therapeutic agents. Journal of
Alzheimer’s Disease 13 (2), 199–223. https://doi.org/10.3233/jad-2008-13210.
Nilson, A.N., English, K.C., Gerson, J.E., Barton Whittle, T., Nicolas Crain, C., Xue, J.,
Sengupta, U., Castillo-Carranza, D.L., Zhang, W., Gupta, P., Kayed, R., 2017. Tau
oligomers associate with inflammation in the brain and retina of tauopathy mice and
in neurodegenerative diseases. Journal of Alzheimer’s Disease 55 (3), 1083–1099.
https://doi.org/10.3233/JAD-160912. PMID: 27716675; PMCID: PMC5147514.
Nordengen, K., Kirsebom, B.E., Henjum, K., Selnes, P., Gísladóttir, B., Wettergreen, M.,
Torsetnes, S.B., Grøntvedt, G.R., Waterloo, K.K., Aarsland, D., Nilsson, L.N.G.,
Fladby, T., 2019. Glial activation and inflammation along the alzheimer’s disease
continuum. Journal of Neuroinflammation 16 (1), 46. https://doi.org/10.1186/
s12974-019-1399-2. PMID: 30791945; PMCID: PMC6383268.
Oberstein, T.J., Taha, L., Spitzer, P., Hellstern, J., Herrmann, M., Kornhuber, J., Maler, J.
M., 2018. Imbalance of circulating Th17 and regulatory T cells in alzheimer’s
disease: A case control study. Frontiers in Immunology 4 (9), 1213. https://doi.org/
10.3389/fimmu.2018.01213.
Parbo, P., Ismail, R., Hansen, K.V., Amidi, A., Mårup, F.H., Gottrup, H., Brændgaard, H.,
Eriksson, B.O., Eskildsen, S.F., Lund, T.E., Tietze, A., Edison, P., Pavese, N.,
Stokholm, M.G., Borghammer, P., Hinz, R., Aanerud, J., Brooks, D.J., 2017. Brain
inflammation accompanies amyloid in the majority of mild cognitive impairment
cases due to alzheimer’s disease. Brain 140 (7), 2002–2011. https://doi.org/
10.1093/brain/awx120. PMID: 28575151.
Park, C., Kupper, T., 2015. The emerging role of resident memory T cells in protective
immunity and inflammatory disease. Nature Medicine 21, 688–697. https://doi.org/
10.1038/nm.3883.
Parkhurst, C.N., Yang, G., Ninan, I., Savas, J.N., Yates 3rd, J.R., Lafaille, J.J.,
Hempstead, B.L., Littman, D.R., Gan, W.B., 2013. Microglia promote learning-
dependent synapse formation through brain-derived neurotrophic factor. Cell 155
(7), 1596–1609. https://doi.org/10.1016/j.cell.2013.11.030.
Pellicanò, M., Larbi, A., Goldeck, D., Colonna-Romano, G., Buffa, S., Bulati, M.,
Rubino, G., Iemolo, F., Candore, G., Caruso, C., Derhovanessian, E., Pawelec, G.,
2012. Immune profiling of alzheimer patients. Journal of Neuroimmunology 242
(1–2), 52–59. https://doi.org/10.1016/j.jneuroim.2011.11.005.
Perry, V.H., Holmes, C., 2014. Microglial priming in neurodegenerative disease. Nature
Reviews. Neurology 10 (4), 217–224. https://doi.org/10.1038/nrneurol.2014.38.
Pietronigro, E., Zenaro, E., Bianca, V.D., Dusi, S., Terrabuio, E., Iannoto, G., Slanzi, A.,
Ghasemi, S., Nagarajan, R., Piacentino, G., Tosadori, G., Rossi, B., Constantin, G.,
2019. Blockade of α4 integrins reduces leukocyte-endothelial interactions in cerebral
vessels and improves memory in a mouse model of alzheimer’s disease. Scientific
Reports 9 (1), 12055. https://doi.org/10.1038/s41598-019-48538-x.
Pirker-Kees, A., Schmied, C., Dal-Bianco, P., 2013. T-cells show increased production of
cytokines and activation markers in alzheimer’s disease. Brain Disord Ther. 3, 1.
https://doi.org/10.4172/2168-975X.1000112.
Prinz, M., Priller, J., Sisodia, S.S., Ransohoff, R.M., 2011. Heterogeneity of CNS myeloid
cells and their roles in neurodegeneration. Nature Neuroscience 14 (10), 1227–1235.
https://doi.org/10.1038/nn.2923.
Prinz, M., Priller, J., 2017. the role of peripheral immune cells in the CNS in steady state
and disease. Nature Neuroscience 20 (2), 136–144. https://doi.org/10.1038/
nn.4475.
Rahman, M.M., Lendel, C., 2021. Extracellular protein components of amyloid plaques
and their roles in alzheimer’s disease pathology. MolNeurodegener. 16 (1), 59.
https://doi.org/10.1186/s13024-021-00465-0.
Ransohoff, R.M., 2016. A polarizing question: do M1 and M2 microglia exist? Nature
Neuroscience 19 (8), 987–991. https://doi.org/10.1038/nn.4338.
Reddy, P.H., Yin, X., Manczak, M., Kumar, S., Pradeepkiran, J.A., Vijayan, M., Reddy, A.
P., 2018. Mutant APP and amyloid beta-induced defective autophagy, mitophagy,
mitochondrial structural and functional changes and synaptic damage in
hippocampal neurons from alzheimer’s disease. Human Molecular Genetics 27 (14),
2502–2516. https://doi.org/10.1093/hmg/ddy154.
Reitz, C., Rogaeva, E., Beecham, G.W., 2020. Late-onset vsnonmendelian early-onset
alzheimer disease: A distinction without a difference? Neurol Genet. 6 (5), e512.
Rizzo, F.R., Musella, A., De Vito, F., Fresegna, D., Bullitta, S., Vanni, V., Guadalupi, L.,
Stampanoni Bassi, M., Buttari, F., Mandolesi, G., Centonze, D., Gentile, A., 2018.
Tumor necrosis factor and Interleukin-1β modulate synaptic plasticity during
neuroinflammation. Neural Plasticity 14 (2018), 8430123. https://doi.org/10.1155/
2018/8430123.
Rossi B, Angiari S, Zenaro E, Budui SL, Constantin G. Vascular inflammation in central
nervous system diseases: adhesion receptors controlling leukocyte-endothelial
interactions. J Leukoc Biol. 2011 Apr;89(4):539-56. doi: 10.1189/jlb.0710432.
Rossi, B., Santos-Lima, B., Terrabuio, E., Zenaro, E., Constantin, G., 2021. Common
peripheral immunity mechanisms in multiple sclerosis and alzheimer’s disease.
Frontiers in Immunology 19 (12), 639369. https://doi.org/10.3389/
fimmu.2021.639369.
Salvador, A.F., de Lima, K.A., Kipnis, J., 2021. Neuromodulation by the immune system:
a focus on cytokines. Nature Reviews. Immunology 21 (8), 526–541. https://doi.
org/10.1038/s41577-021-00508-z.
Sarlus, H., Heneka, M.T., 2017. Microglia in alzheimer’s disease. The Journal of Clinical
Investigation 127 (9), 3240–3249.
M.O. Asamu et al.
Saunders, J.A., Estes, K.A., Kosloski, L.M., Allen, H.E., Dempsey, K.M., Torres-
Russotto, D.R., Meza, J.L., Santamaria, P.M., Bertoni, J.M., Murman, D.L., Ali, H.H.,
Standaert, D.G., Mosley, R.L., Gendelman, H.E., 2012. CD4+ regulatory and
effector/memory T cell subsets profile motor dysfunction in parkinson’s disease.
Journal of Neuroimmune Pharmacology 7 (4), 927–938. https://doi.org/10.1007/
s11481-012-9402-z.
Schlüter, D., Meyer, T., Strack, A., Reiter, S., Kretschmar, M., Wiestler, O.D., Hof, H.,
Deckert, M., 2001. Regulation of microglia by CD4+ and CD8+ T cells: selective
analysis in CD45-congenic normal and toxoplasma gondii-infected bone marrow
chimeras. Brain Pathology 11 (1), 44–55. https://doi.org/10.1111/j.1750-
3639.2001.tb00380.
Schwartz, M., Abellanas, M.A., Tsitsou-Kampeli, A., Suzzi, S., 2022. The brain-immune
ecosystem: Implications for immunotherapy in defeating neurodegenerative
diseases. Neuron 110 (21), 3421–3424. https://doi.org/10.1016/j.
neuron.2022.09.007.
Sengupta, A., Kabat, J., Novak, M., Wu, Q., Grundke-Iqbal, I., Iqbal, K., 1998.
Phosphorylation of tau at both thr 231 and ser 262 is required for maximal inhibition
of its binding to microtubules. Arch BiochemBiophys. 357 (2), 299–309. https://doi.
org/10.1006/abbi.1998.0813.
Sheng, J.G., Jones, R.A., Zhou, X.Q., McGinness, J.M., Van Eldik, L.J., Mrak, R.E.,
Griffin, W.S.T., 2001. interleukin-1 promotion of MAPK-p38 overexpression in
experimental animals and in alzheimer’s disease: potential significance for tau
protein phosphorylation. Neurochemistry International 39 (5-6), 341–348.
Shipton, O.A., Leitz, J.R., Dworzak, J., Acton, C.E., Tunbridge, E.M., Denk, F.,
Dawson, H.N., Vitek, M.P., Wade-Martins, R., Paulsen, O., Vargas-Caballero, M.,
2011. Tau protein is required for amyloid {beta}-induced impairment of
hippocampal long-term potentiation. The Journal of Neuroscience 31 (5),
1688–1692. https://doi.org/10.1523/JNEUROSCI.2610-10.2011.
Smolders, J., Heutinck, K.M., Fransen, N.L., Remmerswaal, E.B.M., Hombrink, P., Ten
Berge, I.J.M., van Lier, R.A.W., Huitinga, I., Hamann, J., 2018. Tissue-resident
memory T cells populate the human brain. Nature Communications 9 (1), 4593.
https://doi.org/10.1038/s41467-018-07053-9.
Stadelmann, C., Albert, M., Wegner, C., Bruck, W., 2008. Cortical pathology in multiple
sclerosis. Current Opinion in Neurology 21, 229–234. https://doi.org/10.1097/01.
wco.0000318863.65635.9a.
Starr, J.M., Farrall, A.J., Armitage, P., McGurn, B., Wardlaw, J., 2009. Blood-brain
barrier permeability in alzheimer’s disease: a case-control MRI study. Psychiatry
Research 171 (3), 232–241. https://doi.org/10.1016/j.pscychresns.2008.04.003.
Steinbach, K., Vincenti, I., Merkler, D., 2018. Tissue-restricted immune residentmemory
T cells in responses: for better or worse? Frontiers in Immunology 9, 2827. https://
doi.org/10.3389/fimmu.2018.02827.
Stojić-Vukanić, Z., Hadžibegović, S., Nicole, O., Nacka-Aleksić, M., Leštarević, S.,
Leposavić, G., 2020. CD8+ T Cell-Mediated mechanisms contribute to the
progression of neurocognitive impairment in both multiple sclerosis and alzheimer’s
disease? Frontiers in Immunology 19 (11), 566225. https://doi.org/10.3389/
fimmu.2020.566225.
Stojiljkovic, M.R., Ain, Q., Bondeva, T., Heller, R., Schmeer, C., Witte, O.W., 2019.
Phenotypic and functional differences between senescent and aged murine
microglia. Neurobiology of Aging 74, 56–69. https://doi.org/10.1016/j.
neurobiolaging.2018.10.007.
Streit, W.J., Sammons, N.W., Kuhns, A.J., Sparks, D.L., 2004. Dystrophic microglia in the
aging humn brain. Glia 45 (2), 208–212. https://doi.org/10.1002/glia.10319.
Sweeney, M.D., Sagare, A.P., Zlokovic, B.V., 2018. Blood-brain barrier breakdown in
alzheimer disease and other neurodegenerative disorders. Nature Reviews.
Neurology 14 (3), 133–150. https://doi.org/10.1038/nrneurol.2017.188.
Taipa, R., Ferreira, V., Brochado, P., Robinson, A., Reis, I., Marques, F., Mann, D.M.,
Melo-Pires, M., Sousa, N., 2018. inflammatory pathology markers (activated
microglia and reactive astrocytes) in early and late onset alzheimer disease: a post
mortem study. Neuropathology and Applied Neurobiology 44 (3), 298–313. https://
doi.org/10.1111/nan.12445. Epub 2017 Nov 27 PMID: 29044639.
Tang, Y., Le, W., 2016. Differential roles of M1 and M2 microglia in neurodegenerative
diseases. Molecular Neurobiology 53 (2), 1181–1194. https://doi.org/10.1007/
s12035-014-9070-5.
Tiemessen, M.M., Jagger, A.L., Evans, H.G., van Herwijnen, M.J., John, S., Taams, L.S.,
2007. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of
human monocytes/macrophages. Proceedings of the National Academy of Sciences
of the United States of America 104 (49), 19446–19451. https://doi.org/10.1073/
pnas.0706832104.
Togo, T., Akiyama, H., Iseki, E., Kondo, H., Ikeda, K., Kato, M., Oda, T., Tsuchiya, K.,
Kosaka, K., 2002. Occurrence of T cells in the brain of alzheimer’s disease and other
neurological diseases. Journal of Neuroimmunology 124 (1–2), 83–92. https://doi.
org/10.1016/s0165-5728(01)00496-9.
Town, T., Tan, J., Flavell, R.A., Mullan, M., 2005. T-cells in alzheimer’s disease.
Neuromolecular Medicine 7 (3), 255–264. https://doi.org/10.1385/NMM:7:3:255.
Trajkovic, V., Stosic-Grujicic, S., Samardzic, T., Markovic, M., Miljkovic, D., Ramic, Z.,
Mostarica, S.M., 2001. interleukin-17 stimulates inducible nitric oxide synthase
activation in rodent astrocytes. Journal of Neuroimmunology 119 (2), 183–191.
https://doi.org/10.1016/s0165-5728(01)00391-5.
Tröscher, A.R., Wimmer, I., Quemada-Garrido, L., Köck, U., Gessl, D., Verberk, S.G.S.,
Martin, B., Lassmann, H., Bien, C.G., Bauer, J., 2019. Microglial nodules provide the
environment for pathogenic T cells in human encephalitis. Acta Neuropathologica
137 (4), 619–635. https://doi.org/10.1007/s00401-019-01958-5.
Unger, M.S., Marschallinger, J., Kaindl, J., Klein, B., Johnson, M., Khundakar, A.A.,
Roßner, S., Heneka, M.T., Couillard-Despres, S., Rockenstein, E., Masliah, E.,
Attems, J., Aigner, L., 2018. Doublecortin expression in CD8+ t-cells and microglia
14
Brain Research 1821 (2023) 148589
at sites of amyloid-β plaques: A potential role in shaping plaque pathology?
Alzheimer’s & Dementia 14 (8), 1022–1037. https://doi.org/10.1016/j.
jalz.2018.02.017.
Unger, M.S., Li, E., Scharnagl, L., Poupardin, R., Altendorfer, B., Mrowetz, H., Hutter-
Paier, B., Weiger, T.M., Heneka, M.T., Attems, J., Aigner, L., 2020. CD8+ t-cells
infiltrate alzheimer’s disease brains and regulate neuronal- and synapse-related gene
expression in APP-PS1 transgenic mice. Brain, Behavior, and Immunity 89, 67–86.
https://doi.org/10.1016/j.bbi.2020.05.070.
Vass, K., Lassmann, H., 1990. Intrathecal application of interferon gamma. Progressive
appearance of MHC antigens within the rat nervous system. AmJ Pathol. 137,
789–800.
Villegas-Mendez A, Greig R, Shaw TN, de Souza JB, Gwyer Findlay E, Stumhofer JS,
Hafalla JC, Blount DG, Hunter CA, Riley EM, Couper KN. IFN-γ-producing CD4+ T
cells promote experimental cerebral malaria by modulating CD8+ T cell
accumulation within the brain. J Immunol. 2012 Jul 15;189(2):968-79. doi:
10.4049/jimmunol.1200688.
Wagner, C.A., Roqué, P.J., Mileur, T.R., Liggitt, D., Goverman, J.M., 2020. Myelin-
specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity. The
Journal of Clinical Investigation 130, 203–213. https://doi.org/10.1172/
JCI132531.
Wattmo, C., Minthon, L., Wallin, Å.K., 2016. Mild versus moderate stages of alzheimer’s
disease: three-year outcomes in a routine clinical setting of cholinesterase inhibitor
therapy. Alzheimer’s Research & Therapy 17 (8), 7. https://doi.org/10.1186/
s13195-016-0174-1.
Webers, A., Heneka, M.T., Gleeson, P.A., 2020. The role of innate immune responses and
neuroinflammation in amyloid accumulation and progression of alzheimer’s disease.
Immunology and Cell Biology 98 (1), 28–41. https://doi.org/10.1111/imcb.12301.
Weiss, R., Lifshitz, V., Frenkel, D., 2011. TGF-β1 affects endothelial cell interaction with
macrophages and T cells leading to the development of cerebrovascular amyloidosis.
Brain, Behavior, and Immunity 25 (5), 1017–1024. https://doi.org/10.1016/j.
bbi.2010.11.012.
Wood, J.A., Wood, P.L., Ryan, R., Graff-Radford, N.R., Pilapil, C., Robitaille, Y.,
Quirion, R., 1993. Cytokine indices in alzheimer’s temporal cortex: no changes in
mature IL-1 beta or IL-1RA but increases in the associated acute phase proteins IL-6,
alpha 2-macroglobulin and c-reactive protein. Brain Research 629 (2), 245–252.
https://doi.org/10.1016/0006-8993(93)91327-o. PMID: 7509248.
Wyatt-Johnson, S.K., Brutkiewicz, R.R., 2020. The complexity of microglial interactions
with innate and adaptive immune cells in alzheimer’s disease. Frontiers in Aging
Neuroscience 19 (12), 592359. https://doi.org/10.3389/fnagi.2020.592359.
Xie, L., Yang, S.H., 2015. interaction of astrocytes and T cells in physiological and
pathological conditions. Brain Research 14 (1623), 63–73. https://doi.org/10.1016/
j.brainres.2015.03.026.
2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 2022 Apr;18(4):700-
789. doi: 10.1002/alz.12638. Epub 2022 Mar 14.
Yang, Y.M., Shang, D.S., Zhao, W.D., Fang, W.G., Chen, Y.H., 2013. Microglial TNF-
α-dependent elevation of MHC class I expression on brain endothelium induced by
amyloid-beta promotes T cell transendothelial migration. Neurochemical Research
38 (11), 2295–2304. https://doi.org/10.1007/s11064-013-1138-5.
Yang, H., Yang, H., Xie, Z., Wei, L., Bi, J., Fiorina, P., 2013. Systemic transplantation of
human umbilical cord derived mesenchymal stem cells-educated T regulatory cells
improved the impaired cognition in AβPPswe/PS1dE9 transgenic mice. PLoS One1 8
(7), e69129.
Yong, V.W., Moumdjian, R., Yong, F.P., Ruijs, T.C., Freedman, M.S., Cashman, N.,
Antel, J.P., 1991. Gamma-interferon promotes proliferation of adult human
astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo. Proceedings
of the National Academy of Sciences of the United States of America 88 (16),
7016–7020. https://doi.org/10.1073/pnas.88.16.7016.
Zenaro, E., Pietronigro, E., Della Bianca, V., Piacentino, G., Marongiu, L., Budui, S.,
Turano, E., Rossi, B., Angiari, S., Dusi, S., Montresor, A., Carlucci, T., Nanì, S.,
Tosadori, G., Calciano, L., Catalucci, D., Berton, G., Bonetti, B., Constantin, G., 2015.
Neutrophils promote alzheimer’s disease-like pathology and cognitive decline via
LFA-1 integrin. Nature Medicine 21 (8), 880–886. https://doi.org/10.1038/
nm.3913.
Zenaro, E., Piacentino, G., Constantin, G., 2017. The blood-brain barrier in alzheimer’s
disease. Neurobiology of Disease 107, 41–56. https://doi.org/10.1016/j.
nbd.2016.07.007.
Zhang, J., Ke, K.-F., Liu, Z., Qiu, Y.-H., Peng, Y.-P., Vitorica, J., 2013. Th17 cell-mediated
neuroinflammation is involved in neurodegeneration of aβ1-42-induced alzheimer’s
disease model rats. PLoS One1 8 (10), e75786.
Zhang, Y., Wang, J., Zhang, Y.i., Wang, L., Wei, J., Chumnanvej, S., 2022. Characteristics
scanning of brain structure and function changes in patients with different degrees of
alzheimer’s disease. Contrast Media & Molecular Imaging 2022, 1–8.
Zhao, M., Cribbs, D.H., Anderson, A.J., Cummings, B.J., Su, J.H., Wasserman, A.J.,
Cotman, C.W., 2003. the induction of the TNFalpha death domain signaling pathway
in alzheimer’s disease brain. Neurochemical Research 28 (2), 307–318. https://doi.
org/10.1023/a:1022337519035. PMID: 12608703.
Zhao, D., Feng, F., Zhao, C., Wu, F., Ma, C., Bai, Y., Guo, J., Li, H., 2018. Role of perforin
secretion from CD8+ t-cells in neuronal cytotoxicity in multiple sclerosis.
Neurological Research 40 (1), 62–67. https://doi.org/10.1080/
01616412.2017.1398371.
Zotova, E., Bharambe, V., Cheaveau, M., Morgan, W., Holmes, C., Harris, S., Neal, J.W.,
Love, S., Nicoll, J.A., Boche, D., 2013. inflammatory components in human
alzheimer’s disease and after active amyloid-β42 immunization. Brain 136 (Pt 9),
2677–2696. https://doi.org/10.1093/brain/awt210.