Free Radical Biology and Medicine 193 (2022) 134–157

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Free Radical Biology and Medicine

journal homepage: www.elsevier.com/locate/freeradbiomed

Altered glucose metabolism in Alzheimer’s disease: Role of mitochondrial

dysfunction and oxidative stress
Saikat Dewanjee a, Pratik Chakraborty a, Hiranmoy Bhattacharya a, Leena Chacko b,
Birbal Singh c, Anupama Chaudhary d, Kalpana Javvaji e, Saumya Ranjan Pradhan f,
Jayalakshmi Vallamkondu f, Abhijit Dey g, Rajkumar Singh Kalra h, Niraj Kumar Jha i, j, k,
Saurabh Kumar Jha i, j, k, P. Hemachandra Reddy l, m, n, o, p, **, Ramesh Kandimalla e, q, *
a
Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700 032, West Bengal, India
b
BioAnalytical Lab, Meso Scale Discovery, 1601 Research Blvd, Rockville, MD, USA
c
ICAR-Indian Veterinary Research Institute (IVRI), Regional Station, Palampur, 176061, Himachal Pradesh, India
d
Orinin-BioSystems, LE-52, Lotus Road 4, CHD City, Karnal, 132001, Haryana, India
e
CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, India
f
Department of Physics, NIT Warangal, Warangal, India
g
Department of Life Sciences, Presidency University, Kolkata, 700073, India
h
Immune Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, 9040495, Japan
i
Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, UP, 201310, India
j
Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India
k
Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
l
Internal Medicine Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA
m
Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
n
Neurology Departments School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
o
Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA
p
Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA
q
Department of Biochemistry, Kakatiya Medical College, Warangal, India

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

Keywords: Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer’s disease
Alzheimer’s disease (AD) (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on
Dementia brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism
Diabetes
associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin
Glucose metabolism
Insulin signaling
signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease
Mitochondrial dysfunction progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we
Neurodegenerative diseases further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol
activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mito­
chondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy.
Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resis­
tance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further
reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work
discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mito­
chondrial dysfunction in the defective cerebral glucose utilization in AD.

Abbreviations: AGEs, advanced glycation end products; Akt, protein kinase B; AMPK, adenosine monophosphate-activated protein kinase; ApoE4, apolipoprotein
E4; APP, amyloid precursor protein; Aβ, amyloid beta; BB, blood-brain barrier; FOX, forkhead box; GLUT, glucose transporter; GSK3, glycogen synthase kinase 3; IDE,
insulin-degrading enzyme; IGF, insulin growth factor; IRS, insulin receptor substrate; mTORC2, mammalian target for rapamycin complex 2; PDK1, phosphoinositide-
dependent protein kinase 1; PGC1-α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphati­
dylinositol (3,4)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; RAGE, receptor for advanced glycation end products; RTK, receptor tyrosine kinase.
* Corresponding author. CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, India.
** Corresponding author. Internal Medicine Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
E-mail address: ramesh.kandimalla@gmail.com (R. Kandimalla).

https://doi.org/10.1016/j.freeradbiomed.2022.09.032
Received 5 August 2022; Received in revised form 16 September 2022; Accepted 29 September 2022
Available online 4 October 2022
0891-5849/© 2022 Elsevier Inc. All rights reserved.
S. Dewanjee et al. Free Radical Biology and Medicine 193 (2022) 134–157

1. Introduction disorders in an age-dependent manner. Altered mitochondrial dynamics,

The occurrence of age-related degenerative disorders has markedly
increased in the last few decades. Progressive dementia and related
neurodegenerative diseases have become a matter of serious concern
among geriatric populations all over the world [1]. Clinical reports of
progressive neurodegeneration together with a gradual loss of cognition
and memory are all symptoms of Alzheimer’s disease (AD), which ac­
counts for almost 80% of dementia cases worldwide [2]. Extracellular
amyloid plaques and intracellular neurofibrillary tangles are the two
major players behind AD onset. However, AD can best be explained as a
multifactorial disorder rather than merely a downstream consequence of
amyloid beta (Aβ) deposition and the formation of neurofibrillary tan­
gles. The progressive decline in glucose utilization in the frontotemporal
cortex during the early stages of dementia indicates the onset of
neurodegenerative diseases [3]. Since glucose is the sole source of en­
ergy in the brain, reduced glucose metabolism affects the brain early and
to a high extent [4]. During AD, mitochondrial and bioenergetic alter­
ations are remindful of those observed with advancing age but are of a
greater extent [5]. The hallmark pathomechanisms of the AD brain
include senile plaques, neurofibrillary tangles, the malfunctioning
cholinergic system, impaired synaptic transmission and plasticity,
oxidative stress, and neuroinflammation [2].
Oxidative stress and genetic mutations contribute to mitochondrial
damage and dysfunction, which in turn, leads to neurodegenerative
including increased mitochondrial fragmentation and defective
biogenesis through modifications in expressions of mitochondria
biogenesis genes typically indicate AD. Biopsy studies have revealed
presence of more mitochondria with broken cristae in AD neurons
compared to age-matched controls [6]. Maintenance of the delicate
balance between mitochondrial fission and fusion is an important factor
for proper bioenergetic regulations. It is important to note here that Aβ
and phosphorylated TAU are critically important for mitochondrial ab­
normalities and oxidative stress in AD. AD is often characterized by
abnormalities in glucose metabolism and respiratory enzymes. The
primary cause of amyloid buildup, mainly Aβ1-42 in AD arises from
misprocessing of amyloid precursor protein (APP), which sets up a chain
of subsequent events that results in the death of neuronal cells [7].
Altered homoeostatic balance resulting from oxidant insult gives rise to
oxidative stress that plays an important role in the progress of AD, or
other neurodegenerative complications [7]. Oxidative stress, in the long
run, induces cellular damage, DNA impairment, and mitochondrial
dysfunction, contributing to age-related degenerative diseases [8–10]. A
growing body of evidence showed the relevance of dysfunctional
glucose metabolism and subsequent oxidative stress plays a key role in
AD progression [11]. Impaired glucose catabolism results in the down­
regulation of ATP synthesis that is involved in this process. On the
mechanistic side, these efforts shed light on the roles of reactive oxygen
species (ROS) and reactive nitrogen species (RNS) in oxidative damage,

Fig. 1. Schematic diagram showing factors involved in the susceptibility to AD. Besides the age, family history, gender, lifestyle, environmental hazards, and
anthropological factors, glucose levels and mitochondrial utilization of glucose play important role in the progression of AD pathology. Aberrant glucose metabolism
and low glucose uptake through the BBB are the significant markers of dementia triggered at a later stages of clinical AD. Aβ, amyloid β; APP, amyloid precursor
protein; BBB, blood-brain barrier; COX, cytochrome oxidase; GLUT1, glucose transporter 1; RCC; regulator of chromosome condensation; ROS, reactive oxy­
gen species.

135
S. Dewanjee et al.
insulin signaling, mTOR activation, and proteostasis abnormalities in
AD brains and underline the need for early detection and antioxidant
interventions in AD [11,12]. However, a synergistic understanding of
these processes with mitochondrial dysfunction/bioenergetic alterations
in glucose metabolism and AD - diabetes mellitus (DM) crosstalk is
elusive. The present work attempts to sum up current knowledge on
these associations among insulin signaling, mitochondrial dysfunction,
and subsequent improper cerebral glucose utilization with AD pathol­
ogies (Fig. 1).
2. Cerebral glucose metabolism: normal versus AD
Reduced brain glucose metabolism has been proposed to be biolog­
ically linked to AD [13]. In healthy brains, glucose is an essential sub­
strate for neuronal cells to gain energy. Brain utilizes more than 20% of
body glucose [14]. The respiratory quotient of the brain is close to 1
indicating carbohydrates as the principal substrate for aerobic meta­
bolism. Transport of glucose across the blood-brain barrier (BBB) and
intracellular catabolism of glucose are two main pillars of cerebral
glucose metabolism, wherein the former requires the help of several
glucose transporters including glucose transporter (GLUT) isoforms
[15]. Thus, insulin, insulin receptors, and insulin-sensitive GLUT iso­
forms provide a platform for insulin-stimulated glucose uptake in certain
brain areas including the hippocampus, a memory-supporting structure
in the brain [16]. Of note, during the stage-wise progression of AD,
cerebral blood flow is compromised by 20–65% and cerebral glucose
utilization is reduced by nearly 45% [17]. Low glucose uptake through
the BBB is a significant marker of dementia that often triggers at a later
stage of AD [18].
Cognitive decline can be directly correlated with reduced glucose
metabolism [19]. Deficiency of glucose transporters i.e., GLUT1 in the
BBB endothelial cells, astrocytes, oligodendrocytes, and neuroglia and
GLUT3 in the neuronal membrane has been evinced to accelerate
cognitive decline through neurodegeneration and Aβ deposition [15].
The Michaelis-Menten constant of GLUT3 is on the lower side which
allows a steady supply of glucose to neurons even at reduced glucose
concentrations towards sustaining brain functions [20]. Microinjection
of glucose into the hippocampus, striatum, amygdala, and medial
septum has been observed to improve memory performance [19]. In a
mouse model of AD, GLUT1 deficiency has been found to accelerate Aβ
deposition leading to neurodegeneration [21]. In a post-mortem brain
study, researchers found higher glucose concentration in early-onset AD
brains along with reduced glycolytic flux and lesser GLUT3 levels [22].
The apolipoprotein E4 (ApoE4) carriers are more prone to hypo­
metabolism of glucose contributing to subsequent cognitive impair­
ments [23]. Additionally, it has been discovered that suppression of
triggering receptors expressed on myeloid cells 2 (TREM2) is linked to
decreased levels of glucose transporters, glycolytic enzymes, and tran­
scription factors that regulate the glycolytic pathway [24]. Reduced
cerebral blood flow and downregulation of glycolytic enzymes, such as
pyruvate dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate
dehydrogenase also play vital roles in AD [25]. AD patients seem to rely
more on anaerobic glycolysis for the generation of energy evidenced by
elevated lactate and reduced pyruvate [26].
2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography
(FDG-PET) analysis demonstrated that adult offspring of AD-affected
mothers are more likely to exhibit AD-like brain abnormalities than
adult children of AD-affected fathers [27]. Since mitochondrial DNA is
acquired from the mother, it established an association between cerebral
glucose metabolism and mitochondria. A correlation between brain
aerobic glycolysis and Aβ deposition has also been established [28].
Evidence-based estimation suggests that nearly 65% of diabetics pose
with increased risk of AD [29]. Within the central nervous system (CNS),
Aβ competes with insulin to interact with insulin-degrading enzyme
(IDE), suggesting that both peptides play an important role to maintain
homeostasis [30,31]. Insulin is involved in maintaining neuroplasticity,
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Free Radical Biology and Medicine 193 (2022) 134–157
and neurotrophic and neuroendocrine functions via GSK-3β signaling
[32]. Resistance to insulin and insulin-like growth factor 1 (IGF1) are
key features of AD that cause a reduction in utilization/catabolism of
glucose and generation of oxidative stress [30].
A high requirement of energy in the brain indicates a small energy
reserve, thereby making the brain highly prone to malfunction on a
compromised supply of glucose and/or oxygen. During compromised
conditions, neuronal firing suffers to a high extent as synaptic functions
require high energy, leading to impaired impulse transduction. To sus­
tain cell viability, the brain tends to shift metabolism towards the con­
servation of energy in the form of ATP. It is, however, beneficial in a
short period, but it may lead to a reduction in brain function and neu­
rodegeneration in the long run. For example, acute reduction in the
activity of α-ketoglutarate dehydrogenase complex aids to minimize
external oxidative stress, while long-term suppression of the activity of
the same results in the AD-like changes in Ca2+ metabolism and impairs
the ability of neurons to sustain the impact of oxidative stress [33].
Deficient glucose uptake in the brain, insulin resistance, and impaired
glycosylation together contribute to compromised glucose metabolism
during AD [34].
Reduced metabolism of glucose in the hippocampal region gradually
spreading to the posterior cingulate cortex, temporal-parietal cortex,
frontal cortex, and occipital cortex indicates the onset and development
of mild cognitive impairment and reduction of synaptic density and
activity. ROS, peroxides, and other free radicals are formed as a result of
the premature leak of electrons to oxygen at electron transport chain
complexes I and III [35]. The imbalance between ROS formation and
scavenging leads to oxidative damage of intracellular lipids, proteins,
and DNA. Subsequently, reduced glucose metabolism in synaptic regions
and reduced production of ATP in mitochondria impairs cytochrome
oxidase (COX) activities [36].
Neuronal glucose utilization decline with age making old age the
most common factor behind AD onset [37]. Impaired glucose uptake and
utilization leads to the lesser formation of acetyl-CoA that ultimately
hampers acetylcholine production and in turn, cholinergic signaling.
Deficient acetyl-CoA also causes neuronal cell membrane abnormality
owing to limited production of membrane lipid components like
cholesterol and other neurosteroids [38]. Impaired glucose metabolism
leads to deficiency of UDP-GlcNAc as well. This, in turn, results in
downregulation of O-GlcNAcylation of microtubule-associated TAU
protein, consequently TAU gets hyperphosphorylated, initiating a
cascade of events for AD onset as observed in the preclinical study [39].
Hyperglycemia due to hypometabolism of glucose compels
auto-oxidation of glucose to form advanced glycation end products
(AGEs) that induce Aβ and TAU, promoting the formation of senile
plaques and neurofibrillary tangles respectively [40].
2.1. Aberrant glucose metabolism: role in amyloid accumulation
Amyloidogenesis refers to a situation where soluble Aβ protein turns
into insoluble fibrillar aggregates. According to the amyloid cascade
hypothesis, proteolytic cleavage of APP by β-secretase and γ-secretase
results in the formation of senile plaques consisting of Aβ1-40 and Aβ1-
42 [41]. The abnormal protein processing leads to the accumulation of
insoluble Aβ aggregates, as a result, downstream AD-related neuropa­
thologies are triggered. Aβ1-42 is more prone to aggregation than
Aβ1-40 [42]. The β-sheet fibrillar conformation of Aβ1-42 is responsible
for the cytotoxic effect. It is to be noted that soluble Aβ oligomers act as
primary neurotoxins impairing glucose metabolism, promoting synaptic
dysfunction by virtue of oxidative damage to the synaptic membrane,
cognitive decline, and affecting learning and memory processes [43].
Glycation, enhances the lifespan of oligomeric forms of Aβ, thereby
facilitating faster cognitive decline, and neuronal death [44]. The
increased presence of C99, a metabolic product of APP, in
mitochondria-associated endoplasmic reticulum membrane (MAM) in­
duces apposition between endoplasmic reticulum (ER) and
S. Dewanjee et al.
mitochondria. It also elevates sphingolipid turnover causing aberrations
in membrane lipid homeostasis in the mitochondria-associated ER
membrane [45].
During the late stages of AD, APP is arrested in mitochondrial protein
transport channels [46]. The accumulation of APP across the mito­
chondrial protein transport channels subsequently impairs membrane
integration leading to an abnormal metabolism in mitochondria and
elevation in H2O2 levels. Increased presence of H2O2 leads to a decreased
activity of pyruvate dehydrogenase and increased lipid peroxidation
even before Aβ deposition, suggesting peroxide-mediated mitochondrial
dysfunction in AD [47]. Accumulation of Aβ via translocase of the outer
membrane (TOM) within mitochondria promotes opening of mito­
chondrial permeability transition pores (MPTPs), which reduces activity
of respiratory chain enzymes, especially complex III and complex IV.
Free radicals produced by these synaptic mitochondria activate β-sec­
retase in late-onset AD, which results in the elevated generation of Aβ
[48]. Compromised production of ATP, in turn, affects neurotransmis­
sion that further aggravates cognitive decline. In the transgenic mouse
models, Aβ has been observed to cause stepwise degradation of synapses
aiding the progress of AD [49,50]. Injection of Aβ in the isolated synaptic
terminal of a neuron has been found to increase ROS levels and leads to
apoptosis in a rat model of early AD [51]. In addition to inactivating
mTORC1 in lysosomes, Aβ can also interact with dynamin-related pro­
tein 1 (Drp1), a mitochondrial fission protein, to impair the normal
mitochondrial dynamics [50].
In AD, functional astrocytes generated from induced pluripotent
stem cells (iPSCs) have been observed to increase oxidative stress in vitro
by increasing the Aβ production [52]. Ca2+ homeostasis and Aβ accu­
mulation are mutually related risk factors behind AD. Aβ1-42 oligomers
increase neuronal Ca2+ levels leading to stress-dependent death of
neuronal cells [53]. A growing body of evidence shows that mitochon­
drial Na+/Ca2+ exchanger (NCLX) is impaired in AD resulting in an
increased accumulation of Ca2+ in mitochondria, which endorses
memory loss and Aβ and TAU accumulation [54]. The genetic rescue of
neuronal NCLX restores the pathological events and cognitive decline
[55]. Age-associated reduction in IDE further aids Aβ accumulation due
to reduced degradation of amyloid aggregates. Increasing ATP produc­
tion by anaerobic pathways is suggested to improve impulse conduction
and accelerate Aβ clearance, thereby could delay the progression of AD
[56].
2.2. Aberrant glucose metabolism: role in TAU pathology
Hyperphosphorylation of TAU proteins produces neurofibrillary
tangles, which is a significant hallmark of AD pathogenesis [57].
Elevated Aβ and ApoE4 levels are responsible for reduced glucose uti­
lization in the AD brain. Cerebral glucose metabolism is affected more
by ApoE4 than ApoE2 [58]. O-GlcNAcylation of TAU is decreased in AD,
as a consequence, TAU phosphorylation is increased. Again, O-GlcNA­
cylation of APP encourages secretion of soluble amyloid precursor
protein alpha (sAPPα) that is rather beneficial for neuronal excitability
and synaptic plasticity [59]. TAU hyperphosphorylation promotes the
self-assembly of paired filaments into tangles that are both helical and
straight in shape, disrupting the stabilized microtubules that are seen
under normal conditions. Suppression of protein phosphatase 2A (PP2A)
in AD brain further supports neurofibrillary degeneration [60]. Cleavage
of inhibitor 2 (I2, also known as SET) of PP2A into I2CTF and I2NTF, and
subsequent translocation from nucleus to neuroplasm initiate AD
development. Introduction of I2CTF into rat brain has resulted in inhi­
bition of PP2A, hyperphosphorylation of TAU, neurodegeneration, and
cognitive decline [61]. Synaptic dysfunctions and progression of TAU
pathology are both facilitated by compromised glucose availability in
the CNS. Deficient glucose metabolism demonstrated memory impair­
ments, long-term reduction of synaptic potentiation, and p38
mitogen-activated protein kinase (MAPK)-mediated increase in TAU
phosphorylation in tauopathy mouse model [13]. Clearly, these reports
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Free Radical Biology and Medicine 193 (2022) 134–157
suggest that the abnormal glucose metabolism in the brain triggers TAU
phosphorylation that is implicated in the pathogenesis of AD.
3. Interlink between insulin signaling and AD
Insulin signaling plays a major role in the proper utilization of
glucose, thus, diabetic patients often experience memory loss and
cognitive impairment [62]. Cerebral glucose metabolism is a mecha­
nistic link between DM and AD. Type 3 diabetes or “brain diabetes”
shares the common molecular and cellular characteristics of type 1 DM,
type 2 DM, and insulin resistance associated with the development of
neurodegeneration [63]. Insulin resistance has been considered as one
of the key characters of both AD and type 2 DM. Brain has higher
number of insulin receptors compared to the rest of the body that are
majorly distributed among the hypothalamus, hippocampus, olfactory
bulb, and cerebral cortex [64]. Insulin receptor substrate (IRS) plays a
major role in learning, memory functions, and synaptic plasticity.
Despite the fact that DM is a peripheral syndrome; while, AD is a CNS
disease, reduced insulin levels are seen in AD brains [65]. Under normal
physiological condition, the brain contains 10–100 times more insulin
than the rest of the body, which is regulated independently [66]. Even
though the exact underlying mechanism is still elusive, and no conclu­
sive theory is yet established. However, studies proposed impaired in­
sulin signaling as a risk factor in AD [67,68].
Insulin is transported through the BBB into the CNS by a specific
transporter system coupled to insulin receptors, abundantly present in
brain microvessels [69]; insulin is also locally produced in the hippo­
campus, cerebral cortex etc. [70,71]. In the brain, insulin signaling is
activated by binding insulin with insulin receptors (IRs). Insulin, on
binding with α subunits of the transmembrane IR, promotes autophos­
phorylation of tyrosine kinases on the β subunits of the receptor. IR
activation endorses phosphorylation and acetylation of IRS1 to accom­
modate phosphatidylinositol 3-kinase (PI3K). While PI3K, in turn,
phosphorylates phosphatidylinositol (3,4)-bisphosphate (PIP2) into
phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3, in conjunction
with the phosphoinositide-dependent protein kinase (PDK) activates
protein kinase B (Akt) by phosphorylating the same. In the hippocam­
pus, Akt1 and Akt3 are scattered throughout the somatic cells, whereas
Akt2 are mostly present in the astrocytes instead of neurons [72].
Phosphorylated Akt, in turn, is responsible for the translocation of
GLUT4 to the plasma membrane to facilitate the intracellular uptake of
glucose. The activation of Akt also suppresses the expression of genes
responsible for phosphoenolpyruvate carboxykinase and
glucose-6-phosphatase aided by forkhead box protein O1 (FOXO1) [73].
Akt simultaneously suppresses glycogen synthase kinase 3β (GSK-3β) so
that glycogen synthase can convert transported glucose into glycogen
without any interruption for storage [74]. Consequently, glycogenesis is
increased while glycogenolysis is downregulated [75]. It also increases
cell survival due to the inhibition of the proapoptotic Bcl2-associated
agonist of cell death (BAD) gene [76]. Interestingly, neoglucogenesis
also takes place within certain brain cells, such as astrocytes, though less
efficient than in the liver [77,78]. Astrocytes are equipped to allow
enzymatic pathways for neoglucogenesis possibly to serve as an alter­
native source of energy for neurons during stressed conditions. Astro­
cytes display sufficient 6-phosphofructo-2-kinase/fructose-2,
6-bisphosphatase activity, which is supported by expressions of the
glucose-6-phosphatase 3 gene in the brain to demonstrate neogluco­
genesis from multiple precursors [77,79,80].
A population-based cohort study found that impaired insulin
signaling causes type 2 DM, which doubles the risk of AD [81]. Both AD
and type 2 DM are amyloid-forming diseases sharing the common fea­
tures of insoluble protein deposition i.e. Aβ in the brain and amylin in
the pancreas respectively [82]. The metabolism of glucose in mito­
chondria is the primary source of energy in brain cells, thus proper
functioning of cognition, memory, learning, neuronal development etc.
are dependent on glucose metabolism. Hypometabolism of glucose in
S. Dewanjee et al.
brain cells acquires the depletion of cognitive abilities gradually leading
to pathological symptoms of AD [23]. It has been reported that geriatric
patients with type 2 DM experience an elevated risk of dementia during
intermittent hypoglycemic states [83].
Insulin facilitates glucose metabolism, defective insulin signaling
leads to decreased glucose metabolism that causes AD symptoms to rise
[36]. AD patients tend to lead a life with up to 80% decreased insulin
compared to normal healthy people [84]. Also, peripheral insulin
resistance has been a very common phenomenon in AD [68]. Insulin
resistance and impaired insulin signaling affect the processing of both
TAU and Aβ, which play important roles in the pathogenesis of AD.
Compromised glucose metabolism cause alterations in APP processing
and produces amyloidogenic depositions [85]. Studies have also estab­
lished a direct connection between Aβ metabolism and insulin signaling
pathways in neuronal cells [57,86]. In a study, insulin-resistant mice
have shown elevated Aβ levels in the brain and an increased amount of
Aβ synthesizing enzymes [87]. Insulin and Aβ are both substrates for
IDE, thereby allowing hyperinsulinemia to competitively inhibit the
degradation of Aβ [88]. Aβ has been experimentally proven to have
detrimental effects on insulin signaling by inhibiting autophosphor­
ylation of the receptors [89,90]. Impaired insulin signaling can also
trigger neurodegeneration by increasing the phosphorylation of TAU
proteins [91]. Of note, insulin and IGF1 regulate TAU phosphorylation
through inhibition of GSK-3β in brain cells [92]. Therefore, impairments
of insulin signaling in the brain results in an increase in GSK-3β activity
by depletion of Akt that leads to hyperphosphorylation of TAU, which in
turn, results in the production of neurofibrillary tangles [57]. Peripheral
hyperinsulinemia has been demonstrated to elevate TAU phosphoryla­
tion [93]. Thus, it is clear that insulin signaling and TAU protein and are
intricately associated, and malfunction in either leads to neuro­
degeneration in AD [94].
3.1. IRS signaling in AD
Insulin upon binding with IR attracts the IRS1 protein. IRS1, being
phosphorylated and acetylated by the activated IR, undergoes confor­
mational changes to accommodate PI3K. PI3K is a key factor in several
subsequent intracellular signaling pathways. Insulin and IGF1 bind with
the IR and IGF1R, respectively to promote tyrosine kinase activities. This
induces tyrosine phosphorylation in cellular substrates including IRS1-4
[95]. Insulin signaling regulates mitochondrial glucose metabolism by
IRS1 and IRS2 [96]. The IRS proteins are constituted with
amino-terminal pleckstrin homology and a phosphotyrosine binding
domain that precedes a tail of tyrosine and serine/threonine binding site
[97]. The structural changes induced in IRS by IR/IGF1R increase the
flexibility of IRS to bind with PI3K [98]. PIP3, a downstream substrate of
PI3K involves the serine/threonine kinase, PDK1 by moving into the cell
membrane, where Akt is activated [99]. The adverse effects of impaired
insulin signaling in the brain are mediated by alterations of protein
functions in IRS by serine/threonine phosphorylation [100].
Insulin triggers tyrosine phosphorylation of IRS1 while serine
phosphorylation of IRS1 is decreased. Both Aβ and insulin resistance
endorses serine phosphorylation of IRS1, implicating a mechanistic as­
sociation of negative and positive regulatory sites of IRS1 in both AD and
DM pathophysiology [100–103]. Other murine models of AD showed
increased serine phosphorylation of IRS1 [105–108]. A growing body of
evidence revealed that abnormal IRS1 serine phosphorylation is linked
to the tauopathy and TAU pathology in AD [103–109]. In the line with
the findings in preclinical AD models and postmortem analyses, human
brain cells also exhibited abnormal serine phosphorylation of IRS1 with
concomitant diminishing total IRS1 and IRS2 protein levels [110,111].
These findings indicate a strong correlation between AD and serine
phosphorylation on IRS1. However, the specific molecular mechanism
of the relationship between IRS1 serine phosphorylation and AD path­
ophysiology remains to be unveiled [111,112].
Accumulating evidence reveals that reduction and/or deletion of
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Free Radical Biology and Medicine 193 (2022) 134–157
IGF1R improves the state of neuronal degeneration in AD, reducing
behavioral deficits and Aβ buildup [113,114]. The impaired IRS2
signaling in brain has been shown to prolong the lifespan, improve
cognitive functions, and decrease Aβ accumulation in preclinical models
of AD under normoglycemic milieu [111,115,116]. The deletion or
suppression of IGF1R does not alter Akt and GSK-3β activities in the
brain of AD mice [117]. Thus, it could be presumed that reduction in
IGF1R/IRS2 signaling exerts neuroprotective action in AD [116].
3.2. PI3K/Akt in AD
PI3K/Akt pathway regulates numerous downstream factors
including GSK3, mTOR complex 1 (mTORC1), and the forkhead box
(FOX) transcription factors that control several essential activities in the
brain and peripheral system [118]. Impaired insulin signaling decreases
P13K activity, which thereby reduces downstream Akt activity. It
cumulatively affects neuronal survival and metabolism [119]. The
drastic decrease in PI3K/Akt activities was observed in the brain cells of
AD patients even in absence of diabetes [120]. In AD brain, the alter­
ations in the insulin/PI3K/Akt signaling seemed to be associated with
decreased phosphorylation or total level of these transcription factors
[65]. A growing body of evidence has shown that Aβ oligomers inhibit
PI3K/Akt pathway and promotes neuronal death [65,121]. Postmortem
AD brains also revealed decreased quantities of IGF1R, IGF1, IRs, insu­
lin, p110, and p85 subunits and reduced phosphorylation of Akt [65,
110]. These alterations are associated with several pathological impli­
cations of AD including the neurofibrillary tangles, microglial and
astroglial markers [119]. PI3K/Akt pathway inhibits activity of GSK-3β,
a TAU-phosphorylating kinase by phosphorylating serine 9 residue
[122] (Fig. 2).
Disruptions of autophagy play a key role in neurodegenerative dis­
orders, which is marked by the accumulation of harmful intracellular
protein aggregates [123]. The mTOR is a key regulator of autophagy,
which forms two complexes, mTORC1, and mTOR complex 2 (mTORC2)
that are interestingly the downstream factors of PI3K/Akt pathway [75,
124]. Phosphorylation of Akt mediated by mTORC2, in turn, triggers
mTORC1 that inhibits autophagy and promotes neuronal protein syn­
thesis [125]. In N2a cells, Aβ expression reportedly seen to acquire in­
sulin resistance, as evidenced by the inhibition of Akt phosphorylation
and increased activity of phosphorylated adenosine
monophosphate-activated protein kinase (AMPK) i.e., negative
mTORC1 regulator [126]. Interestingly in the same study, mTORC2 in
rat primary cortical neurons exhibited the resistance to the effects of
intracellular amyloids.
Under normal conditions, insulin promotes the PI3K/Akt/mTORC1
pathway to suppress autophagy, but when this route is impaired, auto­
phagy increases and the accompanying biomarkers for the development
of AD shift significantly [119]. Chronic low-grade inflammation is a
major pathological feature of both type 2 DM and neurodegenerative
disorders including AD [127,128]. Of note, inflammatory markers, such
as TNF-α are found in blood and the brain samples of AD patients [129].
Hyperinsulinemia can induce neuroinflammation based on increased
levels of TNF-α, IL-1β, and IL-6 in CSF [130,131]. Proinflammatory M1
activation of microglia occurs when toll-like receptor (TLR) 4 is acti­
vated by ligands like lipopolysaccharides. Production and secretion of
proinflammatory cytokines viz. TNF-α, IL-1β, and IL-6 are distinctly
enhanced under activated TLR4 [132]. TLRs also regulate NF-κB via
PI3K/Akt/mTORC1 signaling to influence transcription, cytokines pro­
duction, and survival of immune cells [133].
3.3. GLUTs in AD
Given the fact that glucose is the sole source of energy in the brain,
the defective passage of glucose into brain cells may lead to neurode­
generative pathologies [134]. Insulin stimulates insulin-dependent
GLUTs, GLUT4 and GLUT8 that are abundantly present in the
S. Dewanjee et al. Free Radical Biology and Medicine 193 (2022) 134–157

Fig. 2. Schematic diagram showing PI3K-Akt intracellular signaling. Insulin binding to IR causes tyrosine phosphorylation of IRS and thereby activates PI3K
(composed of regulatory p85 and catalytic p110 subunits). PI3K converts PIP2 into PIP3 that recruits Akt-kinase to cell membrane. PIP3 activates PDK1 to phos­
phorylate Thr308 of Akt1. PI3K/Akt via their downstream factor, viz. Akt substrate 160 kDa (AS160) regulates GLUT4 translocation to the cell membrane and
cellular glucose uptake into the cell, herein mTORC1 regulates several functions including protein synthesis, autophagy, and cell growth/axon growth, GSK3
signaling, glycogen synthesis, and TAU phosphorylation; while, FOX transcription factors regulate functions including cell survival. TREM2, a surface receptor,
signaling in the microglia regulates the phagocytosis, survival, and proliferation. TREM2 is usually activated by lipoproteins, phospholipids, and oligomeric Aβ that
promotes its interaction with DAP12 i.e., activating adaptor protein, which subsequently activates PI3K/Akt pathway. Akt, protein kinase B; AS160, Akt substrate of
160 kDa; DAP12, DNAX activating protein of 12 kDa; FOXO, forkhead box protein O; GLUT, glucose transporter; GRB, growth factor receptor-bound protein 2; GSK-
3β, glycogen synthase kinase 3 beta; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen activated protein kinase; mTORC, mammalian target for
rapamycin complex, PDK1, phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PIP2, phosphatidylinositol (3,4)-
bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; RAF, rapidly accelerated fibrosarcoma; RTK, receptor
tyrosine kinase; Shc, SHC-transforming protein; SHIP, SH2-containing inositol 5′ -phosphatase; SOS, son of sevenless; SYK, spleen tyrosine kinase; TREM2, triggering
receptor expressed on myeloid cells 2.

hippocampus, amygdala, cerebral cortex, and cerebellum. Upon acti­
vation by insulin, GLUT4 translocates from cytosol to cell membrane to
facilitate glucose entry into the cell, whereas GLUT8 translocates to
rough ER within cytosol to retrieve dispensable glucose after the protein
glycosylation. These activities are compromised by downregulated in­
sulin signaling giving rise to neurodegeneration [135]. GLUT1, an
insulin-independent GLUT is present at the BBB, epithelial cells, and
astrocytes. GLUT3 transports glucose into neurons, these transporters
are also present at low levels in endothelial and astroglial cells.
GLUT2 is present at low levels in astrocytes. Some insulin-sensitive
transporters e.g., GLUT4 (hypothalamic neurons, hippocampal neu­
rons, cerebellar neurons, sensorimotor cortex, pituitary), GLUT8 (hy­
pothalamic neurons, hippocampal neurons), and GLUT12 (cortical
astrocytes) are also present in the brain at low levels. Disruption in the
proper functioning of these transporters leads to deficient glucose up­
take by the brain cells, thereby severely affecting the cerebral glucose
metabolism [136]. In AD, deficiency of transport and metabolism of
glucose may be a result of impaired insulin signaling that might occur
due to disturbances in the functioning of insulin-sensitive GLUTs [134].
In a study to understand the correlation between insulin signaling and
GLUTs in AD pathology, it has been found that GLUT1 has a positive
correlation with the insulin signaling proteins, such as IRS1, whereas
GLUT4 has a negative correlation with the same [137]. Insulin signaling
has been found be to positively associated with GLUT1 and GLUT3 ac­
tivities, while an inverse association is seen between insulin signaling
and GLUT2 activity [138,139].
Accumulating evidence suggests that the involvement of GLUTs in
the pathogenesis of AD [140]. A study back in 1989 reported reduced
GLUTs in the neocortex and hippocampal region of the postmortem AD
brain [140]. In the rat model of sporadic streptozotocin-induced AD,
decreased levels of GLUT1 were observed along with impaired insulin
signaling, increased phosphorylation of TAU protein and neurofila­
ments, and decreased microtubule binding capacity of TAU protein
[138]. Reduced levels of GLUT1 in different parts of the brain in
different stages of AD have also been reported in preclinical studies
[141–143]. Reduction of GLUT1 level has been found to hamper glucose
transport leading to TAU phosphorylation, Aβ builds up, and formation
of neurofibrillary tangles [137,144]. Reduction of GLUT3 levels has also
been seen in the AD brains of both humans and rodents [22,142,145,
146]. It has also been seen that GLUT3 inhibition is connected to
reduced insulin signaling, elevated phosphorylation of TAU and neu­
rofilaments, and reduced TAU protein’s capacity to bind to microtubules
[138]. Significant upregulation of GLUT4 and GLUT12 was seen in the
AD brains of both humans and rodents [137,143,147,148]. Increased
level of GLUT2 was observed in the brain of AD rats [139]. Studies have
demonstrated AD-related aggravation as a result of GLUT1 deficiency
that includes a suppression of low density lipoprotein receptor-related
protein 1 (LRP1) level in brain capillary, reduction of Aβ clearing
transporter at the BBB, reduction of the BBB integrity, decrease in ce­
rebral blood flow, enhancement of Aβ accumulation in hippocampus
and cerebral cortex and neuronal impairment and cognitive dysfunction
[21,149].

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3.4. AMPK signaling in AD
AMPK acts as a connecting link between DM and AD. AMPK plays a
key role in the etiology of AD through its influence on glucose and lipid
metabolism, and energy balance. AMPK aids in energy production
through elevated glucose and lipid metabolism and by apprehending
energy-consuming procedures that includes synthesis of cholesterol and
proteins [150]. In insulin signaling, AMPK is closely associated with
neoglucogenesis through both upstream and downstream kinases in the
favor of amelioration of DM [151,152]. The effect of AMPK on insulin
resistance is yet to be unanimously approved by the scientific commu­
nity. Though it is generally considered that AMPK reciprocates insulin
resistance by regulating GLUT4 and free fatty acids, while some re­
searchers have claimed the involvement of AMPK in developing insulin
resistance [153,154]. AMPK is thought to be activated by its upstream
kinases through phosphorylation at Thr172 [155]. AMP: ATP ratio also
plays a vital role in the activation of AMPK-associated metabolic path­
ways. Proteomic analyses have discovered that many of the proteins
dysregulated during AD are closely associated with AMPK signaling
[156,157]. AMPK acts as a metabolic sensor that restores normal brain
energy metabolism and reduces Aβ deposition by modulating β-secretase
[158,159]. It also affects hyperphosphorylation of TAU negatively by
acting upon sirtuin 1 (SIRT1) and PP2A [153]. In addition, AMPK aids in
the alleviation of AD by inducing autophagy to resolve amyloid depo­
sition [160].
In contrast, a non-human primate (female vervet monkeys) model of
AD showed enhanced AMPKα2 activity in the AD hippocampus, while
the activity α1 subunit remained unaltered [157]. However, in a mouse
model of AD, it was observed that genetic reduction of AMPKα1 rescues
cognitive decline better than AMPKα2 [156]. Surprisingly, a similar
APP/presenilin 1 (PS1) mouse model demonstrated metformin to
improve cognitive deficits, presumably through AMPK activation [161].
Sphingosine-1-phosphate and miR (micro-RNA)-590-3 have been re­
ported to boost neuronal apoptosis in AD through AMPK signaling
[162]. The contraindicative observations apprehend a definitive
conclusion on the relationship between AMPK and AD. Activation of
AMPK has been evidenced to delay the aging processes up to a certain
limit and thus it acquires potentially beneficial effects against
age-related neurodegenerative disorders [163]. On the contrary, with
the continuous increase in neuronal stress, AMPK works to trigger and
augment age-related neuropathologies [150]. Due to diminished mito­
chondrial biogenesis and functioning, lower AMPK activity compro­
mises energy balance in the AD brain. Additionally, due to its effect on
APP distribution, cholesterol levels, and sphingomyelin levels, AMPK
can control the production of Aβ [164]. Further, AMPK decreases mTOR
activity to aid in the lysosomal destruction of Aβ by promoting auto­
phagy [165]. Again, AMPK can act as a physiological TAU kinase to
phosphorylate TAU at Ser262, Thr231, and Ser396/404 [166]. How­
ever, to conclude the precise mechanism of AMPK in AD pathophysi­
ology, more research is needed.
4. Defective glucose metabolism mediated by mitochondrial
dysfunction in AD
Neuronal abnormalities mediated by mitochondria are far more
significant in AD pathogenesis than neuroinflammation-induced mito­
chondrial dysfunction. Defective glucose metabolism and impaired in­
sulin signaling in the brain cause mitochondrial dysfunction [167,168]
(Fig. 3). Mitochondrial dysfunction coupled with compromised oxida­
tive activities in mitochondria results in an elevation of ROS accumu­
lation and enhancement of lipid and protein oxidation in the in the
nucleus accumbens and striatum [169]. FDG-PET studies have estab­
lished reduced uptake of glucose into the brain, especially the
temporal-parietal cortex region that shows early symptom of AD prior to
the appearance of other pathologies including cognitive dysfunction
[170,171].
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Free Radical Biology and Medicine 193 (2022) 134–157
Glucose metabolism is mainly dependent on mitochondria to
generate energy. During inefficient oxidation, the ratio of ATP produc­
tion and/or oxygen consumption becomes very low, leading to increased
production of superoxides [172]. Mitochondrial alterations serve as the
primary driving force to malfunction behind insulin resistance, thus
abnormalities in insulin signaling arising from mitochondrial malfunc­
tion are often termed as ‘mitochondrial diabetes’ [173]. On the other
hand, compromised actions of insulin can also dysregulate mitochon­
drial functions [174]. During insulin-resistant conditions, IRSs fail to
inhibit FOXO1, thus hyperactivated FOXO1 induces heme oxygenase 1
(HMOX1) to consume ‘heme’ and disrupt the electron transport chain
leading to increased production of ROS [175]. Downregulation of
NEUROD6 in the AD brain further assists in this cascade [176]. AD brain
witnesses abnormal Kreb’s cycle that causes alterations in oxidative
phosphorylation, resulting in glucose hypometabolism, elevated ROS
generation and apoptosis. Interestingly, mitochondrion itself is highly
susceptible to oxidative stress which allows room to initiate a vicious
cycle [177]. Deposition of amyloids later follows with other manifes­
tations of clinical AD.
4.1. AGEs accumulation and activation of the polyol
AGEs are a group of molecules produced by non-enzymatic in­
teractions between AGEs are a group of molecules produced by non-
enzymatic interactions with carbonyl compounds (glyoxal, methyl­
glyoxal, glyceraldehyde, 3-deoxyglucosone, sugars, etc.) and proteins,
phospholipoprotein, or nucleic acids [178]. The polyol pathway con­
verts glucose to fructose and promotes glycation; fructose is then
transformed to 3-deoxyglucose and fructose-3-phosphate, the two very
powerful non-enzymatic glycation agents [179,180]. Both exogenous
(diet-derived) and endogenous (polyol-pathway-derived) fructose have
been identified as a novel pathogenic factor for a variety of metabolic,
inflammatory, neurodegenerative diseases [181,182]. Hexokinase 1
accumulates in the cytoplasm of murine brain when protein deglycase
(DJ-1) is silenced rather than its usual position in mitochondria [183].
Among the various types of AGEs, acetaldehyde-derived AGEs
(AA-AGEs) are neurotoxic [184]. In cortical neuronal cells,
glyceraldehyde-derived AGE (AGE-2) has powerful neurotoxic effects
nephropathy undergo hemodialysis were entirely decreased by the
addition of an anti-AGE-2 antibody, but not by antibodies against other
forms of AGEs, indicating that AGE-2 could be implicated in neuro­
degeneration [185]. The presence of AGE-2 antigen has been found to be
linked with AD as demonstrated by histological and serum analyses
[185]. AGE-2 is found largely in the neuroplasm of the hippocampus and
parahippocampal gyrus neurons, but not in the senile plaques found in
the brains of AD patients [186]. It has been suggested that AA-AGEs may
play a role in neurodegeneration [187]. When AGEs interact with AGE
receptors, it results in neurodegeneration, which is linked to the etiology
of AD [40]. Increased expression of cathepsin B and asparagine endo­
peptidase (AEP) in the AGE-RAGE axis altered proteome, resulted in an
increase in Aβ production and activation of TAU phosphorylation. These
consequences were seen in AD brain, which coincided with increased
levels of AGEs, establishing a new mechanistic link between AGEs and
AD pathogenesis [40]. Through the generation of AGEs, non-enzymatic
glycation of myelin, or oxidative damage, the role of polyol pathway in
brain abnormalities and cognitive impairment has been hypothesized
[188,189]. Under hyperglycemic circumstances, the polyol pathway
turns glucose into sorbitol by aldose reductase (AR), and subsequently
sorbitol to fructose via sorbitol dehydrogenase (SDH). Increments in
intracellular glucose levels in the hyperglycemic milieu have been
demonstrated to activate the polyol pathway that produces fructose in
insulin-independent organs including the brain [190]. Polyol activation
and concomitant consumption of cofactors NADPH and NAD+ set off a
chain reaction of metabolic abnormalities. AR, nitric oxide synthase
(NOS), and glutathione reductase (GR) all use NADPH as a cofactor and
its depletion inhibits the other enzymes [191]. Reduced NOS activity
S. Dewanjee et al. Free Radical Biology and Medicine 193 (2022) 134–157

Fig. 3. Schematic diagram showing factors involved in the impaired glucose metabolism in the AD pathology. The most prevalent causes of AD are reduced
glucose uptake and utilization, ApoE4 and PS1 mutations, which are characterized by defective glucose utilization in the brains of AD patients. GLUT1 and GLUT3 are
the key glucose transporters that regulate the BBB function and mitochondrial processes including respiration and the Krebs cycle. Alterations in glucose levels
perturb AMPK that subsequently affects Akt-mediated insulin signaling. Mitochondrial dysfunction inhibits PGC-1α that diminishes α-secretase through FOXO3α to
exacerbate Aβ and AD pathology; whereas, AGE interaction with its receptor RAGE promotes Aβ translocation and Tau hyperphosporylation via Akt inhibition, and
activation of GSK-3β. Next, impaired insulin signaling lowers PI3K activity, resulting in reduced Akt activity and increased GSK-β activity that phosphorylates Tau,
promoting Aβ development and deposition. IGF induces insulin resistance and thereby affects Aβ levels and degradation by reducing the levels of IDE. In the
glycosylation defects, O- GlcNAcelytaion and phosphorylation inversely affect the modification of TAU protein, where N-glycosylation stabilizes and modifies TAU
structure. AGEs, advances glycation end products; Akt, protein kinase B; AMPK, adenosine monophosphate-activated protein kinase; ApoE4, apolipoprotein E4
genotype; Aβ, amyloid beta; BBB, blood-brain barrier; GLUT, glucose transporter; GSK-3β, glycogen synthase kinase 3 beta; IDE, insulin-degrading enzyme; IGF,
insulin growth factor; N-GlcNAc, N-acetylglucosamine; PGC1-α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PI3K, phosphatidylinositol 3-
kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PS1, presenilin 1; RAGE, receptor for advanced glycation end products.

and NO content can lead to decreased neuronal blood flow, whereas GR
inhibition causes a reduction in reduced glutathione (GSH), which leads
to an increase in free radical generation and oxidative stress [192].
NAD+ is transformed to the reduced form NADH during the second step
of the SDH-catalyzed process. Because NADH is a substrate for NADH
oxidase, NADH transformation causes an increase in NADH oxidase
activity and the creation of superoxide anions, which further contribute
to oxidative stress [193].
4.2. Defective glucose metabolism in the brain on mitochondrial electron
transport chain and ROS generation
Generation of energy in mitochondria is accomplished through
oxidative phosphorylation in conjunction with electron transfer across
the mitochondrial electron transport chain (terminal respiration) that
includes complexes I through IV and ATP synthase. In the terminal
respiration, final recipient of electrons is oxygen; however, partial
reduction of oxygen may also occur, resulting in potentially cytotoxic
ROS [194]. Because of the high oxygen consumption and low quantities
of endogenous antioxidants, the brain is notably vulnerable to oxidative
damage [195]. Low level of superoxide dismutase (SOD), a mitochon­
drial enzyme that neutralizes superoxide radical, is involved in the
pathogenesis of AD by developing oxidative stress in the brain [196]. In
AD patients, a reduction in SOD-positive neurons in the hippocampus
and frontotemporal cortex has been observed [197]. The brain regions
with a lower density of neurofibrillary tangles and less neuronal loss
showed normal SOD activity in contrast to the severely afflicted regions,
indicating that SOD may be able to inhibit TAU aggregation and
neurodegenerative processes [198]. Multiple subunits of different
complexes of electron transport chain have been recognized in the
extracellular vesicles recovered from the medium of cultured mouse
hippocampus neurons [199]. A growing body of evidence has proposed
structural and functional mitochondrial abnormalities in AD brain cells
[194,199,200]. The patterns of low levels of complexes I, III, IV, and
ATP synthase were also previously recorded in a proteomic investigation
of frozen brain tissue samples of AD patients, but the lower level of
intracellular vesicles was only observed in later stages [201]. Partial
rather than total reduction of oxygen leads to ROS generation, which is
favoured by an imbalance between greater complex IV levels and lower
complex V levels [194]. A study back in 2001 found that neurons with
greater oxidative damage in AD exhibit a remarkable increase in COX
activities [202]. Moreover, the reduced synaptic connection has been
correlated to the mitochondrial level of complex IV, which is increas­
ingly being highlighted as a key aspect of AD pathogenesis [203,204].
ROS interacts with aggregating proteins involved in AD and other
neurodegenerative disorders [12,205]. Neurotoxic Aβ peptides reduce
the levels and activity of complexes I, II, and IV, while it increases ROS
formation that promotes the production of Aβ peptides [200,206]. Aβ
co-localizes with the ATP synthase in the hippocampus and cortex of the
AD brain. This association has also been seen in the plasma membrane

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that results in lower extracellular ATP levels leading to decreased
long-term potentiation (LTP) and increased long-term depression (LTD)
at synapses [207]. Moreover, limiting oxidative metabolism enhances
the amyloidogenic breakdown of APP [194]. Aβ and ROS also syner­
gistically damage synapses, activate microglia and neuroinflammation,
and impair cerebral microvasculature and the BBB functioning [208,
209]. Cytoplasmic SOD1 binds to intracellular Aβ in the brain cells,
generating perinuclear complexes that decrease SOD1 activity [210].
SOD1 deficiency promotes Aβ oligomerization and cognitive/behavioral
impairments; while, SOD1 treatment slows down AD progression and
improves cognition [211].
4.3. Defective glucose metabolism increases mitochondrial permeability in
the brain cells
Enhanced mitochondrial permeability precedes apoptosis. During
oxidative stress, ROS alters mitochondrial membrane potential (MMP)
leading to its depolarization [212]. Resultant pores allow entry of BAD
and cause cytochrome c release to the cytosol. Defective glucose meta­
bolism in combination with greater glucose accumulation leads to
increased ROS generation and activation of NOX and MAPK pathways,
which eventually increase mitochondrial permeability [213]. Mito­
chondrial entry of BAD dislocates B-cell lymphoma 2 (Bcl-2) and en­
courages the release of cytochrome C, which together induce apoptosis
[214]. Additionally, hyperglycemia directly causes mitochondrial
fission and fragmentation, which increases the production of ROS and
triggers the programmed cell death process.
Excess of Ca2+ along with other cellular sensors, such as oxidative
stress, depletion of adenine nucleotides, and excess of inorganic phos­
phate level could endorse the mitochondrial permeability transition
pore (MPTP) to open [215]. MPTP is a non-selective channel that im­
proves the inner mitochondrial membrane permeability to low molec­
ular weight solutes and water. Irreversible MPTP activation, owing to its
non-selective nature, results in severe mitochondrial dysfunction [216].
The prolonged opening of MPTPs results in mitochondrial depolariza­
tion, oxidative phosphorylation uncoupling, and excessive formation of
ROS [217]. In addition, unregulated entry of tiny osmolytes and water
into mitochondria via MPTPs results in mitochondrial swelling, which
disrupts the outer mitochondrial membrane [216]. Increased mito­
chondrial permeability also promotes cell death pathways by depleting
energy currency of cells and allowing cytochrome C to leak from the
inter-membrane space [218,219]. It has been found that abnormal
glucose phosphorylation products and ROS are responsible for mito­
chondrial dysfunction in AD. ROS is also a key regulator of MPTP. One
possible mechanism for ROS-mediated MPTP formation is the estab­
lishment of aqueous channels by oxidatively altered transmembrane
proteins with the aid of cyclophilin D (CypD) to promote mitochondrial
membrane permeabilization [220,221].
ROS-induced ROS release is an intriguing notion in the context of
ROS-mediated opening of MPTPs on reaching ‘the mitochondrial
permeability transition (MPT)-ROS threshold. MPTPs trigger the release
of mitochondrial ROS into the cytosol, where they subsequently interact
with the adjacent mitochondria [222]. The mechanism of MPT signal
amplification still exists even after the ROS-inducing cell stress are
removed, leading to an MPT propagation across all mitochondria [223].
Through this mechanism, MPTP propagation also causes mitochondrial
Ca2+ dysregulation, and Ca2+ leakage from damaged mitochondria in­
creases the role of ROS in driving MPTP activation in nearby mito­
chondria. It results in severe mitochondrial stress and, in the worst
scenario, the induction of an intrinsic apoptotic pathway [224].
CypD expression always remains higher in the AD brains of both
humans and animals [225,226]. Though the role of adenine nucleotide
translocase (ANT) in the formation of MPTP is still debated, mass
spectrometry examination of brain samples from patients with mild
cognitive impairment and AD revealed overexpression of ANT [227].
These findings imply a propensity for MPTP activation as seen in the
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rodent model of AD, given the inhibitory effect of CypD depletion and
oligomycin-sensitivity-conferring protein (OSCP) overexpression on
MPTP opening in Aβ-rich settings [228,229]. Indeed, in brain mito­
chondria from animal models with AD-like brain amyloidosis as well as
in Aβ-insulted cells, enhanced sensitivity of MPTP opening is noticeable
[230,231]. Excess parenchymal Aβ build-up results from disruptions in
Aβ metabolism, including increased synthesis and impaired breakdown
[232]. The interaction between Aβ and CypD activates MPTP in the
brain mitochondria, resulting in mitochondrial malfunction and neural
stress [228,233]. F1F0 ATP synthase uncoupling and MPTP opening are
mediated by the development of an Aβ/oligomycin sensitivity conferral
protein (OSCP) complex, as observed in the AD brains, hence OSCP is
also a binding partner of Aβ [229,234]. Surprisingly, Aβ strengthens
CypD and OSCP-related MPTP formation in Aβ-rich environments by
enhancing CypD regulation of OSCP by boosting their interaction [226,
229]. A specific role for Aβ in promoting MPTP formation is shown by
the interaction of Aβ with MPTP-forming/regulating proteins, as well as
by the effects of Aβ on neuronal Ca2+ dysregulation and oxidative stress
in AD-related pathological conditions [235]. Apart from Aβ, hyper­
phosphorylated TAU aggregation is another hallmark of AD brains
[236]. TAU also influences MPTP through promoting mitochondrial
dysfunction and enhancing mitochondrial ROS production [237]. In
human brain tissues, neurotoxic amino-terminal (NH2)-derived TAU
interacts with ANT and the ANT/CypD complex, promoting the
Aβ/ANT/CypD supercomplex [238]. Importantly, TAU silencing reduces
MPTP opening and suppresses CypD expression [239]. These findings
establish a link between TAU and MPTP in AD.
4.4. Defective glucose metabolism in the brain cause defect in PINK1/
parkin
Phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)
functions as a metabolic sensor coupling biogenetics of cells and stress
signals to mitochondrial dynamics. Level of PINK1 in healthy mito­
chondria is very low due to proteases and ubiquitin ligases. Under stress
conditions e.g. elevated ROS levels, depolarized mitochondrial mem­
brane, increase in misfolded proteins, etc. PINK1 accumulates in the
outer mitochondrial membrane [240]. Parkin is selectively recruited
into dysfunctional mitochondria with low MMP to execute mitophagy.
PINK1-dependent mitochondrial recruitment of parkin in response to
mitochondrial damage requires active glucose metabolism [241]. De­
fects in parkin recruitment can be correlated with suppression of PINK1
upregulation in response to mitochondrial depolarization. Parkin
mitochondrial translocation and maintaining high PINK1 levels during
mitophagy are crucially regulated by ATP. Low levels of ATP arising
mainly from improper utilization of glucose, appear to prevent PINK1
translation [242]. Moreover, respiratory chain defects lead to loss of
PINK1 causing a decrease in MMP and enhanced sensitivity to oxidative
stress [243].
PINK1 and parkin play their roles in Ca2+ homeostasis [244]. Cyto­
solic PINK1 initiates transduction cascades that result in the suppression
of autophagy/mitophagy and the promotion of neuronal branching by
activating the mTORC2/Akt and protein kinase A signaling pathways.
Mitochondrial respiration defects in the cerebral cortex and aconitase
inhibition in the striatum have been found to be associated with PINK1
silencing [245]. Interference with PINK1 has been found to increase
sensitivity to oxidative stress owing to mitochondrial dysregulations.
PINK1 is also involved in the impairment of the electron transport chain
leading to reduced oxygen consumption. At a metabolic level, loss of
PINK1 significantly inhibits glucose uptake by pancreatic primary islets
including β-cells that is accompanied by increased insulin secretion and
enhanced glucose tolerance [246].
Drop in MMP initiates the translocation of parkin. On reaching to
damaged mitochondria, parkin ubiquitinates membrane fusion protein,
mitofusin-2 leading to proteasomal degradation of the same to prevent
the fusion of damaged mitochondria with the healthy mitochondria
S. Dewanjee et al.
[247]. Depolarized mitochondria cannot fuse, thus excessive fission
leads to small fragments that easily fall prey to autophagosomes and/or
lysosomes. Mitochondrial degradation follows, aided by p62 protein and
protein 1 light chain 3 (LC3) signaling. MUL1 also acts simultaneously to
complement the removal of dead mitochondria along with parkin/­
PINK1. Accumulating evidence demonstrate the protective role of
PINK1 against neurodegeneration mediated by oxidative stress, pro­
teasomal activities, ER stress, and mitochondrial dysfunction. Interest­
ingly, translocation of parkin from cytosol causes decreased proteasomal
activities in cytosol leading to accumulation of TAU, Aβ, etc. PINK1
plays a crucial role in balancing mitochondrial fusion and fission.
Overexpression of PINK1 promotes mitochondrial fission, while its in­
hibition is found to trigger mitochondrial fusion [248]. Under normal
conditions, a low level of PINK1 is maintained, however, stresses like
elevated ROS level and depolarized mitochondrial membrane tends to
cumulate PINK1 at the outer mitochondrial membrane. In contrast, a
study proposed that the recruitment of PINK1 by hexokinase 1 and 2
under stressed conditions stabilizes the outer mitochondrial membrane,
while depolarizing the inner one [249]. Mitochondria-associated ER
membrane is upregulated in AD. Interestingly, they are considered to
initiate autophagy as the isolation membrane forms at this site [250].
This site also produces necessary proteins for the formation of Aβ from
APP. Parkin and parkin interacting substrates suppress the biogenesis of
mitochondria through suppressing gene expression within the cell nuclei
[251]. Mitochondria-specific autophagy is closely linked to glucose
metabolism through AMPK and mTOR signaling [252]. Under hypoxic
conditions, FUN14 domain-containing 1 interacts with micro­
tubule-associated LC3 via specific motifs present on it to form auto­
phagosomes to incite mitophagic activity.
4.5. Defective glucose metabolism in brain lysosome-mitochondrial
crosstalk and autophagy
Lysosome-mitochondria crosstalk is impaired in neurodegenerative
disorders. Mitochondria are associated with the production of energy,
while lysosomes process cellular wastes. Autophagy is a catabolic pro­
cess mediated by autophagosomes, whereby non-functional components
are transferred to lysosomes for digestion/destruction. Stress and hyp­
oxia are among the chief activators of autophagy which is controlled by
a number of signaling pathways, including mTOR, FOXO, and insulin
signaling [75,253]. Lysosome autophagy dysfunctions affect the proper
functioning of other organelles including the mitochondria, leading to
an excess of ROS resembling pathological features associated with aging,
chronic inflammation, and neurological diseases [254]. Immature
autophagosome accumulation and dystrophic neurites have been found
in the brains of AD patients [255]. Autophagosomes are predominantly
accumulated in the dendrites rather than in the soma [256,257]. Amy­
loid pathology of AD is preceded with autophagosome accumulation;
however, their clearance is compromised by downregulation of various
autophagy-related proteins as observed in the brains of AD mice [258,
259]. These findings suggest that defective or compromised autophagy
contributes in AD pathogenesis.
Autophagy influences Aβ metabolism by regulating the production
and clearance of Aβ [260]. Aβ is formed by the cleavage of the precursor
protein APP by the enzymes β-secretase and γ-secretase [261]. Auto­
phagy related 7 protein (ATG7) functions as an E1-like enzyme in
autophagosome formation for ubiquitin-like conjugation. Extracellular
Aβ synthesis is significantly reduced by ATG7 silencing and autophagy
deficiency [262]. Additionally, Aβ secretion is hindered by autophagy
disruption [263,264]. A recent clinical study found that human subjects
with deleterious ATG7 variations exhibit a variety of neuro­
developmental problems [265]. Surprisingly, two variant carriers under
the age of 30 years were found to have poor learning abilities, suggesting
a potential correlation between dysfunctional autophagy and impaired
cognition [265].
Microglial endocytosis is thought to be involved in the clearance of
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Free Radical Biology and Medicine 193 (2022) 134–157
extracellular Aβ [266–268]. Knock-in of a point mutation F121A of
beclin-1 endorses autophagy by preventing the association of beclin-1
with its inhibitor Bcl-2, which endorses amyloid oligomer sequestra­
tion resulting in reciprocation of cognitive impairment [269]. In a pre­
ceding experiment, beclin-1 silencing has been found to endorse the
accumulation of both intraneuronal and extracellular Aβ aggregation
[270]. Autophagy appears to influence Aβ clearance at various stages.
Cathepsin B is a lysosomal protease that is essential for breakdown of
autophagic substrates. Ablation of cathepsin B gene has been found to
A
exacerbate AD pathology and increases β42 accumulation [271]. These
observations suggest that autophagic flux could be beneficial for miti­
gating AD progression.
Selective autophagy, in addition to bulk autophagy, has been
discovered to play a role in Aβ metabolism. Normally, Aβ binds to
ubiquitin to create a complex that prevents formation of insoluble fibrils
[272]. Apart from Aβ metabolism, autophagy plays an important func­
tion in TAU homeostasis. Autophagy is likely to affect tauopathies as
well. Interruption of autophagic flow has been shown to impair TAU
clearance and endorse insoluble TAU clump accumulation [273]. In the
brains of familial AD patients, hyperphosphorylated TAU has been found
to be colocalized with the autophagosome marker LC3 and the auto­
phagy receptor p62/SQSTM1 (sequestosome 1), but not in healthy
controls [274]. In a cell line-based study, immunoreactivity to LC3 and
p62/SQSTM1 was consistently linked to TAU aggregates [275]. Indeed,
TAU phosphorylation was found to be significantly increased in condi­
tional ATG7 knockout mice, presumably due to the build-up of GSK3 i.e.,
one of the major TAU kinases in the brains of ATG7 knockout mice
[276].
Aβ clearance is also modulated by autophagy. The mTOR inhibitor
rapamycin drastically reduced intracellular and extracellular amyloid
buildup in the brains of AD mice, which resulted in a notable
improvement in cognition by restoring autophagy [277,278]. Auto­
phagy induction also ameliorates tauopathies, in line with its role in Aβ
metabolism [279]. Rapamycin treatment to TAU-mutant mice exhibited
considerably less extent of TAU phosphorylation [277,278]. Tuberous
sclerosis complex 2 (TSC2) is a negative regulator of mTOR, thus TSC2
silencing significantly activate mTOR signaling, resulting in a higher
accumulation of phosphorylated TAU in the brain of experimental ani­
mals [280]. In addition to the aforementioned findings, other research
showed that autophagy activation could aid in the prevention of tauo­
pathies in AD [281–283]. The autophagy receptor NDP52 (nuclear dot
protein 52 kDa), in addition to p62/SQSTM1, has been preclinically
found to recognize phosphorylated TAU in the AD brains [284].
Increased production of NDP52 by its upstream transcription factor
nuclear factor erythroid 2-related factor 2 (Nrf2) endorses the break­
down of phosphorylated TAU [285]. In addition to mTOR and auto­
phagy receptors, transcription factor EB (TFEB), one of the key
autophagy regulators is thought to play a role in TAU-mediated disor­
ders. TFEB upregulation has been shown to reduce soluble phosphory­
lated TAU and insoluble TAU clumps and improved cognitive
functioning [286]. According to a recent study, TFEB regulates TAU
exocytosis in lysosomes, which promotes TAU clearance [287]. In TAU
P301S transgenic PS19 mice, conditional silencing of TFEB resulted in
lower TAU quantity in the interstitial fluid but higher intraneuronal TAU
phosphorylation, and increased TAU spreading [288].
C-terminus of TAU has two motifs that can be recognized as sub­
strates for chaperon-mediated autophagy (CMA). TAU mutants, on the
other hand, are still targeted to lysosomes via lysosome-associated
membrane protein 2 (LAMP2A) oligomerization. However, TAU mu­
tants cannot reach all the way into the lysosomal lumen, instead mutant
TAU proteins can enter the lysosomal lumen partially [289]. The lumen
sections are then destroyed and the smaller fragments on the lysosome
membrane oligomerize and impede CMA [289,290]. TAU acetylation is
resistant to CMA-mediated degradation and tauopathies are exacerbated
when CMA is compromised [291]. The same research group experi­
mentally revealed that loss of CMA accelerates TAU aggregation and
S. Dewanjee et al.
increases disease development, whereas increasing CMA activity by
drugs dramatically mitigates AD pathology [292]. In the etiology of AD,
the accumulation of Aβ produces an abundance of ROS and damages
mitochondria; wherein damaged mitochondria are usually eliminated
by mitophagy [293–295]. When the MMP collapses due to too much
ROS, mitophagy is activated in mammals. The PINK1-Parkin route is a
well-studied MMP-dependent mitophagy pathway. In normal func­
tioning mitochondria, PINK1 is translocated into the mitochondrial
matrix. However, in the injured mitochondria, the weakened MMP
prevents PINK1 from being imported and keeps it on the outer mito­
chondrial membrane, where it is autophosphorylated and activated
[296,297]. Parkin and ubiquitin are phosphorylated and activated by
activated PINK1 [298,299]. Parkin detects the phospho-ubiquitin on
outer mitochondrial membrane as an E3 ligase, causing increased parkin
recruitment [300]. Typically, autophagy receptors p62/SQSTM1 and
optineurin identify ubiquitinated mitochondria, which subsequently
initiate autophagic destruction [301]. Parkin is proven to be unessential,
as phosphorylated ubiquitin produced by PINK1 is sufficient for auto­
phagy receptor NDP52 and optineurin recognition [302]. PTEN-L, a new
isoform of PTEN, was identified as a critical negative regulator of
PINK1/parkin-mediated mitophagy [303]. PTEN-L is discovered to
inhibit mitophagy by dephosphorylating parkin and ubiquitin through
its intrinsic phosphatase activity [304]. Multiple different kinds of
mitophagy have been reported in addition to PINK1-parkin mediated
mitophagy, demonstrating the complexity of mitochondrial homeostasis
maintenance. Consequently, mitochondrial dysfunction is identified as a
common sign of AD [295,301,305].
In post-mortem study of AD patients showed suppression of hippo­
campal mitophagy [34,306]. Since mitochondrial failure is an early
pathological aspect of AD and entorrhinal cortex is the first region to be
impacted by AD, it has been proposed that dysfunctional mitophagy in
the entorhinal cortex could be an early hallmark of AD pathology [306].
Similar phenotypes were found in preclinical model of AD and neurons
produced from induced pluripotent stem cells of AD patients, implying
that mitophagy activation could help to slow the progression of AD
[209,307]. In this line, pharmaceutical mitophagy agonists have been
proven to be useful to treat AD [307]. The findings showed that
increased mitophagy improved the cognitive capabilities of AD by
alleviating both Aβ and TAU abnormalities. Thus, mitophagy-mediated
clearance of defective mitochondria would have therapeutic potential
for AD intervention.
5. AD and DM crosstalk
AD and type 2 DM both share the common pathology of insoluble
protein depositions i.e. Aβ in the brain and amylin in the pancreas
respectively [308]. Combined with the classic plaque and tangle pa­
thology, glucose hypometabolism and associated pathophysiological
alterations initiate a chain of factors contributing to the exacerbation of
AD. Progressive decline of cerebral glucose metabolism rate precedes AD
onset [309]. The correlation between reduced glucose utilization and
the pathogenesis of AD is known to the scientific community since the
1980s, associating the reduced rate of cerebral glucose metabolism with
worsened disease pathology [310]. DM, mainly type 2 DM enhances the
risk of AD significantly, wherein oxidative stress plays a key role [309].
In the brain, the active involvement of oxidative stress in insulin resis­
tance and AMPK dysfunctions was highlighted earlier to acquire neu­
rodegeneration by promoting neurotoxicity [164]. A detrimental effect
of that on the proteins regulating insulin signaling leading to metabolic
dysfunctions by AMPK dysregulation was suggested to be critically
involved in AD-associated metabolic pathways [164]. Progressive loss of
glucose metabolism in the frontotemporal dementia Fpi3indicates the
onset of neurodegenerative diseases. Thus, glucose metabolism largely
serves a mechanistic link between DM and AD. AMPK connects DM and
AD by playing a key role in the development of AD through modulating
glucose and lipid metabolism, and energy balance. Intracellular entry of
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glucose in the brain, like other regions is largely mediated by
insulin-dependent GLUTs, which makes insulin an important player in
brain energy metabolism. In the hypothalamus, DM-associated insulin
resistance triggers autophagy to ultimately boost the progression of
neurodegenerative disorders. Amyloidogenesis, impaired brain insulin
signaling, abnormal brain glucose metabolism, mitochondrial dysfunc­
tion, and oxidative stress are common denominators in both AD and DM
that potentiate brain dysfunction [82].
Reduced levels of Nrf2 and compromised synaptic integrity are
common factors in cases of DM and AD. Impaired mitochondrial respi­
ration and altered MMP have been revealed to be characteristic etiol­
ogies of AD in type 2 DM [311]. High cerebral superoxide levels
contribute to the initiation of AD [312]. Overexpression of ApoE4 has
been demonstrated to hinder insulin-stimulated mitochondrial respira­
tion by interacting with IRs in an age-dependent manner [313]. The
resultant decrease in the ATP generation and increment in protein
phosphorylation leads to the exacerbation of pre-existing AD conditions.
Mitochondrial dysfunction aided by insulin resistance generates high
oxidative stress leading to improper glucose metabolism, and the for­
mation of amyloids in the CNS. On the other hand, generated Aβ and
oxidative stress further exacerbate mitochondrial dysfunction,
hampering glucose homeostasis to a greater extent. Insulin activates
PI3K/Akt pathway to restore insulin-signaling and promotes mito­
chondrial biogenesis to improve cognition in DM-associated neuronal
disorders [314]. Interestingly, since insulin resistance is a common
causative factor in both AD and type 2 DM, the antidiabetic drugs have
shown positive effects in the treatment of AD [315].
Abnormal cerebral glucose metabolism and mitochondrial dysfunc­
tion can be blamed upon decreased activities of mitochondrial thiamine-
dependent enzymes e.g. pyruvate dehydrogenase complex and α-keto­
glutarate dehydrogenase complex modulating crucial aspects of brain
glucose metabolism that are critical to the normal functioning of the
brain [250]. A study reported depletion of pyruvate dehydrogenase
complex, α-ketoglutarate dehydrogenase complex and isocitrate dehy­
drogenase, and increased activities of succinate dehydrogenase and
malate dehydrogenase during AD, while other enzymes of Kreb’s cycle
remained unaltered [316]. Lessened or incomplete aerobic metabolism
of glucose might lead to oxidative stress and consequent mitochondrial
dysfunction in the brain neurons [317].
6. Mitochondrial involvements and oxidative stress in AD
Mitochondrial dysfunction is deeply connected to the generation of
ROS and mitochondria-driven apoptosis, which appear to be aggravated
in the brain of AD patients [318]. ROS concentration beyond the
clearance capacity of cells leads to oxidative stress, mitochondrial
dysfunction, cellular damage, and cell death. Thus, it suggests oxidative
stress as a possible common mechanism underlying age-related diseases
like AD. Since neurons contain a lot of polyunsaturated fatty acids and
have a high oxygen need for energy, they are often quite vulnerable to
oxidative stress. In addition, neurons also have a weak antioxidant de­
fense. Thus, neurons are critically sensitive to mitochondrial conditions
and alterations that underlines role of mitochondria as the master
coordinator of energy metabolism and a major producers of ROS [319].
Situation becomes further exacerbated as mitochondria themselves are
highly susceptible to ROS [224]. Oxidative stress upregulates β-secretase
expression through c-jun N-terminal kinase (JNK) and p38 MAPK
signaling to promote TAU phosphorylation via GSK-3β [320]. Mito­
chondria are intricately involved in the regulation of redox signaling,
Ca2+ homeostasis, and synaptic plasticity thereby purposefully influ­
encing cell survival [321]. Activated MAPKs critically contribute to
synaptic deficits in AD cybrid cells via further augmentation of mito­
chondrial oxidative stress and consequent mitochondrial dysfunction
[322]. Oxidative stress tends to shift the balance of apoptotic regulations
towards neuronal death and thus promoting neurodegeneration [323].
Impairments of mitochondrial gene expressions include genes
S. Dewanjee et al.
responsible for complex IV of the electron transport chain, p53 protein,
and NADPH oxidase that regulates the severity of AD [324]. Mutations
in the presenilin 1 cause an imbalance in Ca2+ metabolism in ER leading
to mitochondrial dysfunction and implicated in familial AD. Crosstalk
between mitochondria and ER deleteriously affects neurodegeneration
as both produce ROS and compromise antioxidant defense [325].
Extracellular accumulation of Aβ alters glutaminergic neurotransmis­
sion via (N-methyl-D-aspartate) NMDA receptors resulting in a
concomitant hike in cytosolic Ca2+, and impairment of synaptic activity.
Increased Ca2+ is rapidly taken up by the mitochondria and ER and this
overload encourages ROS formation.
Higher than normal oxidative stress is a common observation in the
AD brain. The effect of oxidative stress on the progression of AD was first
noted back in 1965 [27,326]. ROS-controlled lipid peroxidation pro­
duces toxic malonaldehyde in the brain that causes DNA damage [327,
328]. Post-mortem examinations have revealed an abundance of
oxidized cellular macromolecules in AD brain [329,330]. Simultaneous
accumulation of 8-oxoG responsible for initiating cell death pathways
and Aβ in the hippocampus and temporal cortex of AD brain further
supports the interrelation between oxidative stress and AD [331,332].
Mitochondrial Aβ deposition starts well ahead of extracellular plaques to
disrupt the respiratory chain by disturbing oxidative phosphorylation
[225]. While dysfunction in the electron transport chain of mitochon­
dria characterized by a selective reduction in COX activities has been
observed in platelets, lymphocytes, and post-mortem brain tissue of AD
patients [333,334]. Impaired COX of the mitochondrial electron trans­
port chain produces more H2O2 than usual when exposed to oxidative
stress, making it itself a powerful tool of ROS generation [335].
Aβ is primarily responsible for the beginning of mitochondrial
dysfunction. Aβ induces mitochondrial dysfunction either by interacting
with Aβ binding alcohol dehydrogenase (ABAD) or by localizing into
cristae by virtue of translocase present in the outer mitochondrial
membrane [336]. In an AD mouse model, reduced activity of ABAD was
observed due to the mitochondrial localization of ABAD-Aβ conjugate
resulting in elevated ROS levels and consequent mitochondrial impair­
ment [337]. Aβ alters mitochondrial membrane permeability and re­
duces enzyme activity involved in mitochondrial respiration to initiate
mitochondrial dysfunction leading to an oxidative stress and subsequent
neuronal damage [8]. Normal mitochondrial activity is also hampered
by the inhibition of APP in the mitochondria. A study has demonstrated
that inhibition of the respiratory chain complexes causes an elevation of
Aβ formation predominantly dependent on augmented ROS levels
[338]. Early pathogenic characteristics of AD include synaptic
dysfunction and synaptic loss, which are likely caused by abnormalities
in synaptic mitochondria [339]. In this context, post-mortem examina­
tion of AD patients has revealed an increase in oxidative biomarkers
localized in the synapses indicating the important role of oxidative stress
in AD-associated synaptic decay [340]. The presequence protease (PreP)
suppression decreases the cleavage of Aβ in the temporal lobe of AD
patients, which could be attributed to the high levels of lipid peroxi­
dation [341]. In the AD brain, nerve impulse transduction and synaptic
plasticity are compromised as a result of an imbalance in Ca2+ homeo­
stasis. Aβ and TAU play their parts by compromising the capacity of
mitochondria to handle Ca2+ metabolism properly leading to enhanced
oxidative stress, altered MMP, decreased MPTP formation, and lowered
ATP production [342]. Upstream of these events, an imbalance in
intraneuronal Ca2+ activities promotes Aβ aggregation, which again aids
in releasing Ca2+ from ER to further increase cytosolic Ca2+ [342].
Dementia and progressive cognitive decline are the two main fea­
tures of AD. Most experts approve that neurodegeneration plays a sig­
nificant role in the gradual loss of memory and other cognitive
impairments [343,344]. The concomitant mitochondrial degeneration,
which is frequently brought on by numerous neuro-immune reactions,
makes the situation even more severe. The interaction of ROS, TAU
protein, and APP potentiates the formation of neurofibrillary tangles
and Aβ depositions [41]. Beginning in the hippocampus and gradually
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spreading throughout the brain, neurofibrillary tangles impair memory,
judgement, and speech [345]. Aβ aggregations originating from APP in
extraneuronal space trigger the immune system to initiate neuro­
inflammation. Pathogen recognition receptors like CD14, CD36, α6β1,
and TLRs are employed to regulate the activities of ROS, NO, and cy­
tokines [346]. Moreover, AD cybrids have demonstrated mitochondrial
dysfunction as evidenced by reduced activities of COX and elevated
production of free radicals [347,348]. Post-mortem analysis of AD brain
cells reported decreasing amounts of COX subunits with the disease
progression [349]. It has also been noted that elderly AD patients
possess lower levels of COX in comparison to younger AD patients [350].
These findings imply that COX decreases with ageing and may eventu­
ally pass a threshold, which may be associated with and contribute to
the pathogenesis of AD [351]. By blocking COX with N-methyl­
protoporphyrin, control fibroblasts were induced to undergo AD-like
alterations, demonstrating that oxidative damage in AD substantially
coincides with mitochondrial dysfunction [347]. AD brain with
increased numbers of COX-deficient neurons further supports this hy­
pothesis [352].
With aging, intracellular oxidative stress tends to increase owing to
the bioenergetic imbalance and mitochondrial dysfunction. Activity of
oxoguanine (oxoG) DNA glycosylase declines in aging brain that com­
promises repairing capacity of nucleic acid damage due to modification
of the enzyme by 4-hydroxynonenal, i.e., a bi-product of ROS-mediated
lipid peroxidation that promotes the formation of 8-oxoG [327,353].
Lipid peroxidation and production of 4-hydroxynonenal in neuronal and
mitochondrial membranes are influenced by Aβ1-42 oligomers, which
subsequently alters protein structures and functions. Smaller oligos can
more easily penetrate lipid bilayers than bigger ones, which increases
the risk of oxidative damage [11]. The loss of LTP and subsequent
oxidative damage to synaptic membranes caused by Aβ oligomers ulti­
mately impact learning and memory processes. Oxidative damage to
synapses causes malfunctioning in interneuron communications, cyto­
skeletal dynamics, and neuronal plasticity [354]. Aβ-mediated in­
crements in ROS and RNS trigger a series of molecular events through
TGF-β, NOX, and NF-κB signaling favoring the onset of AD [355]. Free
radical-mediated TAU phosphorylation destabilizes neuronal microtu­
bules that in turn, hampers synaptic conductivity. The regular func­
tioning of the cells is hampered by peptides that are prone to
aggregation as a consequence of oxidative damage to mitochondrial
nucleic acids [351]. Elevated oxidative stress also hampers cholinergic
transmission by the reduction in cholinergic transporters and receptors
mainly in the hippocampus and neocortex [356]. Increased expression
of matrix metalloproteinase-9 controlled by elevated ROS level, in turn,
favors AD development by allowing entry of inflammatory factors and
more ROS through the BBB into CNS [357].
Elevated oxidative stress oxidizes the bases in the mitochondrial
nucleic acids that could serve as markers for AD, wherein 8-oxoG is found
to be the most prominent among all [66]. Immunohistochemical evalua­
tion of postmortem AD brains revealed neuroplasmic accumulation of
8-oxoG in hippocampal Cornu Ammonis (CA)1 and CA3 pyramidal and
temporal cortex neurons where Aβ is also highly accumulated [168].
2-deoxyguanosine is oxidized to 8-hydroxy-2-deoxyguanosine and subse­
quently to 8-oxo-dGTP (8-Oxo-2′ -deoxyguanosine-5′ -triphosphate) that is
mismatched to an adenine nucleotide converting guanine (G)-cytosine (C)
base pair to thymine (T)-adenine (A) base pair [358]. Interestingly, C can
be converted into uracil (U) by oxidative deamination and pair with A
instead of G, thus replication leads to the formation of T-A instead of C-G
base pair [359,360].
Glucose is the sole source of energy for neurons and ROS play a role
in this aspect as well. Lower expressions of GLUT1 in the BBB and GLUT3
in neurons mediated by ROS allow lesser transport of glucose into the
CNS and inside nerve cells, giving rise to glucose hypometabolism in the
brain [361]. AD neurons reportedly display elevated oxidative stress and
mitochondrial autophagy that leads to decreased mitochondrial mass
and increased mitochondrial DNA in the cytosol. Increased COX level in
S. Dewanjee et al.
lipofuscin vacuoles has also been observed [36]. Although oxidative
stress and inflammation are not exclusive to AD, the pathologies overlap
extensively to contribute to the progression of AD. Amyloids are pro­
posed to limit mitochondrial function at later stages to increase oxida­
tive stress and neuroinflammation, despite the fact that oxidative
damage caused by mitochondria and the related inflammatory response
are implicated in the development of AD [362].
7. Hypometabolism-mediated bioenergetic alterations in AD
The pathophysiology of AD has been widely associated with
disturbed bioenergetics, including elevated mitochondrial oxidative
stress and impaired glucose metabolism. Energy metabolisms become
dysfunctional with age, especially in neurodegenerative diseases like
AD. Reduction in brain metabolism occurs before the depositions of Aβ
and neurofibrillary tangles in AD. AD patients with glucose hypo­
metabolism exhibits its onset from the hippocampus that gradually
spread to parieto-temporal lobe, posterior cingulate cortex, and the
frontal areas of the brain [363,364]. This also justifies the initial tran­
sient dementia during AD as the hippocampus is responsible for memory
functions. Disruption of the pyramidal neurons in the perforantal path
aids to disconnect the hippocampus from the rest of the cortex, strongly
contributing to the memory decline as observed during the early stages
of AD [365]. During AD, glycolysis and Krebs cycle, both are compro­
mised mainly due to the poor performance of the pyruvate dehydroge­
nase complex [366]. AD also involves the reduction in synaptic density
and activity impairing impulse transduction, thinner axons with reduced
myelin sheath also add to deficient impulse transduction [367]. These
neurons require higher energy thus hypometabolism associated with AD
could be correlated with this pathophysiology. FDG-PET scanning can
differentiate between the initial stage of AD and non-AD related de­
mentia [368]. ApoE4 and presenilin 1 genes are suggested to be the
important players in the development of AD and glucose hypo­
metabolism at the temporoparietal and posterior cingulate cortex acts as
a key contributor [369]. It is also claimed that cerebral hypometabolism
of glucose may be associated with grey matter atrophy [370]. However,
during cognition disorders, hypometabolism of glucose and Aβ are
regulated independently from each other [351]. Moreover, elevated
production of ketone bodies has been observed during AD [371].
Hypometabolism of glucose during AD enforces metabolic shift in the
brain from glucose to lipid for survival, which again correlates with
amyloid and TAU pathology [372].
Neurodegenerative disorders are highly susceptible to mitochondri­
opathy owing to the dependency of nerve cells on oxidative phosphor­
ylation to meet their high energy demands [373]. Aβ can act directly on
mitochondria and interact with ABAD which may cause mitochondrial
failure by increasing the MMP and reducing the activities of enzymes
involved in mitochondrial respiration [336]. Again, the interaction of Aβ
with CypD and COX enhances ROS production by disturbing the electron
transport chain. These interactions also decrease the generation of ATP
and thus affect energy production [374]. Aβ also interferes with Krebs
cycle enzymes e.g., pyruvate dehydrogenase, malate dehydrogenase,
and aconitase [375]. Antioxidant activities are also disrupted in AD
since Aβ interferes with SOD and catalase. However, the mitochondrial
cascade hypothesis proposes that impairment of the respiratory chain
and bioenergetic mechanisms are more important players in the AD
development than Aβ pathologies [200].
Although neurons depend on oxidative phosphorylation for long-
term survival, impairment of mitochondrial functions enforce them to
switch more to glycolysis for energy production [376]. Inverse Warburg
hypothesis postulates AD as a downstream consequence of mitochon­
drial dysregulation [377,378]. Thus, a malfunction in the respiratory
chain and bioenergetics of mitochondria leads to the cell stress response,
changes in neurotransmitters, excessive ROS production, disrupted Ca2+
homeostasis, Aβ buildup, activation of NF-κB, inflammation and
neuronal cell death [379]. Astrocytes and neural progenitor cells from
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Free Radical Biology and Medicine 193 (2022) 134–157
late-onset AD patients reportedly evinced multiple inter-related bio­
energetic alterations, such as alterations in glycolysis, alterations in
bioenergetic substrate processing and transfer of reducing agents,
reduced levels of NAD/NADH, downregulated glucose uptake and
response to INS/IGF-1 signaling, decreased population of INS receptor
and GLUT1, and changes in the metabolic transcriptome [380].
The ATN (Aβ deposition, TAU phosphorylation, and neuro­
degeneration) standard is cementing its place in the diagnosis of AD
clustering neuroimaging techniques with standardized indicators [381].
Proteomic data in the animal model have suggested dysregulation of
glucose metabolism in AD liver [382]. AD lymphocytes exhibit increased
apoptosis [383–385]. In peripheral mononuclear blood cells of AD pa­
tients, basal mitochondrial oxygen consumption was reduced, while
dATP levels were increased [386].
8. Interconnection between impaired glucose metabolism and
mitochondrial dysfunction in AD
Mitochondrial dysfunction associated with impaired glucose meta­
bolism is viewed as significant contributing factor in the AD pathology.
Patients with AD have fewer mitochondria per neuron, even the existing
mitochondria differs in shapes and morphologies [243]. Glucose hypo­
metabolism and mitochondrial dysfunction collectively give rise to
several other pathophysiological factors namely oxidative stress, Aβ
build-up, TAU hyperphosphorylation, apoptosis, AGEs accumulation,
and excitotoxicity [170]. Insulin can directly affect mitochondrial
glucose metabolism by activating pyruvate dehydrogenase that is vitally
involved in bridging glycolysis and Kreb’s cycle.
It has been observed that impaired insulin signaling in the AD brain
gives rise to mitochondrial dysfunction due to severe impairment in
glucose metabolism [387]. AD and type 2 DM share common features
like inflammation, oxidative stress, and impaired glucose and insulin
metabolism. Evidence from FDG-PET imaging has revealed that glucose
uptake in the temporal-parietal cortex gets hampered in AD patients
even before the appearance of cognitive and behavioral symptoms
[388]. Abnormal basal phosphorylation levels of proteins in the IRS/Akt
pathway were also seen in different studies, involving post-mortem AD
brains. These abnormalities contribute positively to Aβ and TAU lesions
and negatively to memory and cognition. Insulin resistance was revealed
to be associated with Aβ and TAU lesions independent of cognitive and
memory functions in the hippocampal region [103,120]. Contemporary
research also supports the notion that mitochondria are the primary
metabolic platforms of cell’s malfunction during insulin resistance [389,
390]. In the IRS/P13K/Akt cascade, Akt phosphorylates FOXO tran­
scription factors responsible for gene expressions regarding lipid meta­
bolism, neoglucogenesis, and stress resistance [391]. IRSs are strong
inhibitors of FOXO1 through Akt-mediated phosphorylation in the liver.
Insulin resistance causes hyperactivation of FOXO1 that in turn, induces
HMOX1 to consume heme to disturb the integrity of the electron
transport system within mitochondria leading to excessive ROS pro­
duction [390,392]. ROS induces oxidative stress giving rise to several
neurodegenerative factors including the mutations of mitochondrial
DNA, apoptosis, and build-up of oxidative lesions [393]. Two essential
metabolic actions of mitochondria i.e., Kreb’s cycle and oxidative
phosphorylation are found to be severely affected in AD brains [168].
This gives rise to not only the hypometabolism of glucose but also an
increase in the production of ROS, oxidative damage, and apoptosis.
Studies found that the aging-related hypometabolism in mitochondria is
different from the hypometabolism due to AD as age-related hypo­
metabolism occurs in the medial-lateral cortex, while AD majorly in­
duces hypometabolism in the lateral frontal cortex [170,394]. The AD
pattern of glucose hypometabolism that precedes the clinical manifes­
tation elevates, expands, and worsens through the clinical deterioration
ensues.
Impaired glucose metabolism in brain cells, specifically modified
thiamine metabolism and insulin resistance might be responsible for
S. Dewanjee et al. Free Radical Biology and Medicine 193 (2022) 134–157

promoting Aβ build-up and TAU hyperphosphorylation [395]. These central insulin resistance, impaired cerebral glucose metabolism, and
cascades are directly involved in AD pathophysiology and cognitive mitochondria failure may represent a dangerous trio in AD
dysfunction. During AD, mitochondria cannot consume pyruvate as fast pathophysiology.
as it is produced by glycolysis, as a result, lactate accumulation leads to
toxic acidosis [304]. Insulin resistance leads to excess activation of 9. Discussion
GSK-3β, this may activate β-secretase activity to result in increased
cellular accumulation of Aβ [396]. Alterations in thiamine metabolism The prevalence of neurological diseases is rising in tandem with the
led to a build-up of Aβ plaques and hyperphosphorylation of TAU. TAU increase in the aged population globally. Progressive dementia along
hyperphosphorylation and the formation of neurofibrillary tangles can with cognitive deficiencies characterize AD. Extracellular amyloid de­
also be induced by glucose transporter abnormalities. Insulin resistance posits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic
promotes TAU hyperphosphorylation through the P13K/Akt pathway abnormalities, oxidative stress, and inflammation contribute to the gross
[397] while reducing E2K exaggerates plaque formation and memory cerebral bioenergetic malfunction in AD brain. During AD, signaling
deficits in animal models of AD [316]. The interruption of metabolism pathways including AMPK, IRS, mTOR, NF-κB, and SIRT1 in combina­
leads to hyperphosphorylated TAU and the production of Aβ1–42 [398]. tion mediate amyloid aggregation, inflammation, and mitochondrial
The reduction of glucose metabolism leads to activation of β-secretase, energy dynamics. Table 1 enlists biomarker-specific alterations during
which is critical to aggregation of amyloids [399]. Glycolysis in astro­ AD. A few studies proposed amyloids and TAU toxicity as upstream
cytes may also have a role in amyloid accumulation and cytotoxicity. events of mitochondrial dysfunction, while others claimed them to be
Inhibiting astrocytic glycolysis and associated lactate shuttle results in downstream events of abnormally functioning mitochondria [411,412].
an accumulation of amyloid protein and vulnerability to The proper functioning of both neurons and glial cells is critical in
amyloid-related cytotoxicity [400]. Insulin is also considered to be a neurodegenerative disorders. DM has been associated with neuronal
factor in the degradation of Aβ outside cells by altering the activity of dysfunction and cognitive decline, increasing the risk of developing AD.
IDE [401]. Amyloidogenesis, impaired brain insulin signaling, abnormal brain
The requirement and production of energy are much higher in the glucose metabolism, mitochondrial dysfunction, and oxidative stress are
brain than other organs in the body. This requires great share of mito­ common denominators in AD and DM that potentiate brain dysfunction.
chondrial activity, and any disruption to it can produce mitochondrial Volume losses in the hippocampus, entorhinal cortex, and para­
dysfunction as well as oxidative stress. Oxidative markers such as 8- hippocampal gyrus are repeatedly displayed during the development of
hydroxyguanosine is usually observed before hallmark features of AD- AD from mild cognitive impairment.
like Aβ precipitates and neurofibrillary tangles [402]. In AD, iron Gradual loss of cholinergic neurons, excessive oxidative stress, and
deposition has been reported to building up oxidative stress that causes
protein and DNA oxidation, and inactivation of brain muscarinic re­
ceptors required for memory [403]. Table 1
Apoptosis can be mediated by AD-related pathogenesis, such as AD-associated modulations in the brain.
oxidative stress, altered phosphorylation, mitochondrial DNA muta­ Sl Biomarkers Associated pathways Type of modulations
tions, etc. The neurons with AD-specific mutations are sensitive towards No.
mitochondrial toxin-induced apoptosis [310]. It has also been observed 1 Aldolase Glycolysis Downregulation
that Aβ encourages the release of cytochrome c from mitochondria in AD 2 ATP synthase Oxidative Downregulation
neurons, which induces neuronal apoptosis [404]. Glucose hypo­ phosphorylation
metabolism also leads to inflammation in brain tissues and enhances the (electron transport
chain)
pathological expression of AD. The inflammatory factors are the results
3 Aβ plaques Synaptic impulse Upregulation
of critical insults that include Aβ build-up, oxidative stress, and mito­ transduction
chondrial dysfunctions [405,406]. Suppression of autophagy in the 4 Caspases Neuronal apoptosis Upregulation
brain due to hypometabolism of glucose leads to CNS degeneration and 5 Complex I Oxidative Downregulation
phosphorylation
exacerbates the pathology of AD [407]. Another important stimulus for
(electron transport
autophagy is mTOR which can sense metabolites as well as hormonal chain)
signaling. mTOR is also involved in AD pathology as enhanced mTOR 6 Complex IV Oxidative Downregulation
signaling increases Aβ deposits and neurofibrillary tangles in the brain phosphorylation
[150]. Impaired glucose metabolism disrupts the uptake of glutamates (electron transport
chain)
via astrocytes giving rise to excitotoxicity, an early event in AD brains
7 Enolase Glycolysis Upregulation
[408]. 8 Lactate Glycolysis Upregulation
Serum profiling study has identified 12 deregulated proteins in AD dehydrogenase
patients including phosphoenolpyruvate carboxykinase 2, adenylate 9 Malate Kreb’s cycle Upregulation
kinase 2, heat shock protein family A member 9, cytochrome C, somatic, dehydrogenase
10 Phosphoglycerate Glycolysis Downregulation
dihydrolipoamide dehydrogenase, glycine amidinotransferase, etc. mutase
[409]. To add, AD pathology involves dysregulation of oxidative phos­ 11 Pro-apoptotic Neuronal apoptosis Upregulation
phorylation, inducible NOS (iNOS), and NF-κB signaling. proteins
Ridge and colleagues earlier have prepared a database of mito­ 12 Pyruvate Glycolysis Downregulation
dehydrogenase
chondrial genomes to aid future research on mitochondrial association
13 Pyruvate kinase Glycolysis Upregulation
with neurodegenerative disorders [410]. Since mitochondria are the 14 RNS Oxidative stress Upregulation
central coordinators of energy metabolism and are sources and targets of 15 ROS Oxidative stress Upregulation
ROS, their impairment may constitute a downstream event of DM 16 Succinate Kreb’s cycle Upregulation
and/or AD-associated abnormal brain insulin and glucose metabolism. dehydrogenase
17 TAU Synaptic impulse Hyperphosphorylation
Defective insulin signaling makes neurons energy-deficient and more transduction
vulnerable to oxidizing insults, which could cause structural and func­ 18 Trios phosphate Glycolysis Upregulation
tional alterations in mitochondria. Aβ and hyperphosphorylated TAU isomerase
synergistically impair mitochondrial bioenergetics and potentiate 19 α-ketogluterate Kreb’s cycle Downregulation
dehydrogenase
oxidative stress, accelerating neurodegenerative mechanisms. Overall,

147
S. Dewanjee et al.
formation of misfolded proteins form the base of AD. Research results
from a rigorous mouse model of AD suggest that AMPK activators could
be viable drug candidates for the treatment of AD [413]. Multi-target
therapy collectively comprising of anti-aging pathways mentioned
earlier holds strong promise for impaired cellular metabolic processes in
AD. Future might belong to double-impact therapeutic avenues meant
for both DM and AD. With the translation of renewed insight into the
mechanisms regarding cellular and mitochondrial abnormalities into
novel therapeutic alternatives against neuronal degeneration, it would
minimize the gap between basic science and clinical research for AD.
10. Inference
Malfunctions in cerebral glucose metabolism kickstart a series of
pathological events gradually leading to neurodegenerative disorders
including AD. Mitochondria, via multiple signaling pathways, play vital
roles in glucose metabolism. Clearly, mitochondrial dysfunction is an
important factor in the reduced utilization of glucose. Combined with
the classic plaque and tangle pathology, glucose hypometabolism and
associated pathophysiological alterations initiate a chain of factors
contributing to the initiation and exacerbation of AD. Glucose hypo­
metabolism supplemented with other factors like insulin resistance and
mitochondrial dysfunction plays crucial roles in AD pathogenesis.
Multiple mitophagy pathways co-exist for the clearance of non-
functional mitochondria, contributing factors include genetics, protein
expressions, and stress responses. AD pathology might be reversed by
inhibiting excessive mitochondrial division, or by enhancing mitophagy.
To translate the scientific knowledge gathered so far into investigative
clinical practice, a revised focus on novel therapeutic and/or prophy­
lactic advancements is urgently needed.
Acknowledgements
The study project (grant number 02(0275)/16/EMR-II) that was
given to S.D. by the Council of Scientific and Industrial Research, New
Delhi, India, is appreciated by the authors. For the State government
Research Fellowship (Reference No. R-11/13/20), P.C. acknowledged
Jadavpur University. The facilities provided by Jadavpur University in
India are gratefully acknowledged by all the authors. For the Ram­
alingaswami Fellowship, R.K. thanked DBT, India (NO. BT/RLF/Re-
entry/22/2016), Kakatiya Medical College, Warangal, SAN.No. 102/
IFD/SAN/1117/2018–19, and CSIR-IICT Hyderabad. J.V. and R.K.
acknowledged DBT for the grant-No.BT/PR35841/MED/32/745/2020.
P.H.R. likes to express his heartfelt thanks to NIH for his projects
(R01AG042178, R01AG47812, R01NS105473, AG060767, AG069333,
and AG066347). Finally, the authors are grateful to the editor and re­
viewers for their in-depth analyses and insightful criticism, which aided
the scientific quality of this project.
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