Journal of Alzheimer’s Disease 61 (2018) 487–508 487

DOI 10.3233/JAD-170187
IOS Press

Review

Tauopathies: Mechanisms and Therapeutic

Strategies
Chen-Chen Tan1 , Xiao-Yan Zhang1 , Lan Tan∗ and Jin-Tai Yu∗
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University,
Qingdao, Shandong, China

Accepted 15 September 2017

Abstract. Tauopathies are morphologically, biochemically, and clinically heterogeneous neurodegenerative diseases defined
by the accumulation of abnormal tau proteins in the brain. There is no effective method to prevent and reverse the tauopathies,
but this gloomy picture has been changed by recent research advances. Evidences from genetic studies, experimental animal
models, and molecular and cell biology have shed light on the main mechanisms of the diseases. The development of
radiology and biochemistry, especially the development of PET imaging, will provide important biomarkers for the clinical
diagnosis and treatment. Given the central role of tau in tauopathies, many treatments have constantly emerged, including
targeting phosphorylation, targeting aggregation, increasing microtubule stabilization, tau immunization, clearance of tau,
anti-inflammatory treatment, and other therapeutics. There is still a long way to go before we obtain drug therapy targeted at
multifactor mechanisms.

Keywords: Biomarkers, mechanisms, neurodegenerative diseases, tau, tauopathy

INTRODUCTION integrate and interpret recent advances that have pro-

Tauopathies are believed to be involved in dozens
of neurodegenerative diseases, clinically manifesting
with a wide spectrum of symptoms, including cog-
nitive, behavioral, or motor impairments [1]. They
are histopathologically defined by the filamentous
inclusions of unusually phosphorylated tau protein
in neurons and neuroglia [2]. Recently, mechanisms
and therapeutic strategies of tauopathies become a
hot spot in this field. The discoveries of biomarkers
of tauopathies open up a new avenue for revealing
the real roles of tau in mechanisms of neurode-
generative diseases and provide effective evidences
for clinical treatments [3]. In this review, we will
1 Theseauthors contributed equally to this work.
∗ Correspondence to: Lan Tan and Jin-Tai Yu, Department of
Neurology, Qingdao Municipal Hospital, School of Medicine,
Qingdao University, No. 5 Donghai Middle Road, Qingdao,
Shandong Province 266071, China. E-mails: dr.tanlan@163.com
(Lan Tan); yu-jintai@163.com (Jin-Tai Yu).
vided new clues for mechanisms and therapeutics of
tauopathies. Moreover, we also discuss the promising
and novel therapeutic strategies for other neurode-
generative disorders with the lessons learned from
the recent knowledge of tauopathies.
TAU ISOFORMS AND GENETICS
Tau is a member of microtubule-associated pro-
tein family which is concentrated in axons of central
nervous system and peripheral nervous system, and
plays a physiological role in dendrites [4]. Located
on chromosome 17q21, a single gene containing 16
exons (E) encodes the human tau proteins. Six tau iso-
forms have been formed by alternative splicing of E2,
3, and 10 (Fig. 1A). The alternative splicing of E2 and
3 produces three tau isoforms-two N-terminal inserts,
one insert or no insert, while the alternative splicing
of E10 generates two tau isoforms-3R (three repeat

ISSN 1387-2877/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved
488 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
Fig. 1. Tau six isoforms and mutation of MAPT in human brain.
A) Six tau isoforms are produced via inserting a 29-aminoacid
or 58-aminoacid encoded by E2 (light brown) and E3 (brownish
yellow) in the N-terminal half and by the presence or absence of
31-aminoacid repeat domains encoded by E10 (brown) in carboxy-
terminal half. The alternative splicing E2 and E3 produces three
tau isoforms-2N (two N-terminal inserts), 1N (one insert) or 0N
(no insert). The alternative splicing of E10 generates two tau
isoforms-3R (three microtubule-binding repeat domains) or 4R
(four microtubule-binding repeat domains). E1, 4, 5, 7, 9, 11,
12, and 13 (grey) constitute the basic component of tau protein,
whereas E0, 4a, 6, 8, and 14 are not. B) Mutations of MAPT genes,
mainly relation with frontotemporal dementia and parkinsonism
linked to chromosome 17. 55 sites mutations in MAPT including
43 exon mutations and 15 non-coding-region mutations flanking
E10 are revealed. MAPT, microtubule-associated protein tau.
domains) or 4R (four repeat domains) [5]. Except
promoting the formation of microtubules and keeping
their stability, tau also plays a key role in maintain-
ing neuronal architecture and axonal transport and
serves as an anchor for enzymes of cell signaling or
other proteins. Meanwhile, it regulates cell activity
and viability [6].
A great majority of genetic studies put focus on
the mutation of MAPT and related genes. Mutation
of MAPT and related genes promote tau aggregation,
reduce its affinity for microtubule, disturb the bal-
ance between 3R and 4R and regulate the splicing of
mRNA [7], leading to tauopathies. Over 50 mutations
on MAPT, which is located on 17q21-22, have been
identified to date [4] (Fig. 1B). Mutations in E9-12
increase the mRNA splicing, leading to tau hyper-
phosphorylation, tangle formation, synapse loss, glial
activation, neuronal loss, and memory impairment
[7–9]. Missense mutations of MAPT jeopardize phys-
iological functions of tau protein and facilitate the
aggregation of microtubule. Nearly 80% of mis-
sense mutations are associated with frontotemporal
dementia and other neurodegenerations including
progressive supranuclear palsy (PSP), Pick’s dis-
ease (PID), and corticobasal degeneration (CBD)
[10]. Mutations of R406W and A152T are found
to be associated with both FTDP-17 and AD-like
pathological process [11, 12]. A152T increases the
levels of p-tau protein and decreases clearance of
p-tau protein. A152T substitution increases the risk
of neurodegeneration by increasing p-tau levels and
enhancing network hyperexcitability, combined with
other pathogenic factors [13]. Interestingly, the same
mutation was linked with distinct syndromes in the
same family; for example, the son has the clinical
manifestation of CBS while the father has frontotem-
poral dementia (FTD) [4].
Two haplotypes, including H1 with a 900-kb
inversion polymorphism and H2 with non-inversion
polymorphism, also contribute to the neurodegenera-
tive diseases. H1 causes PSP and Parkinson’s disease
as well as CBD through H1c. H1c is located in one of
intron 0 regulatory region of MAPT. Recent studies
have shown that MAPT H1c haplotype (rs242557)
is a genetic risk factor for CBD and PSP [14]. H2
confers protection by increasing E3 expression of
MAPT in grey matter [15]. KANSL1 is a gene encod-
ing chromatin modifier which affects the expression
of gene via the lysine 16 acetylation of histone H4.
Its haploinsufficiency causes 17q21.31 microdeletion
syndrome [16]. Additionally, the mutations in 18q
deletion syndrome and other 21 genes have been
reported to be related to tauopathies. In the other
21 genes, some genes (ATP6AP2, SLC9A6, LRRK2,
PRKN, SNCA, and CYP27A1) were detected to occur
with tauopathy through some “specific” mutations.
Others (including CLN6, CNBP, DMPK, ITM2B,
NPC1, NPC2, PANK2, PRNP, PSEN2 and SLC17A5)
were detected to form AD-like neurofibrillary tangles
(NFTs) in tauopathy (Table 1) [17].
CLINICOPATHOLOGICAL FEATURES
OF THE TAUOPATHIES
Tauopathies are morphologically, biochemically,
and clinically heterogeneous neurodegeneration
 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
Genetic mutation with tau pathology
Diseases
Alzheimer’s disease (AD)
Argyrophilic grain disease (AGD)
Corticobasal degeneration (CBD)
Frontotemporal dementia and parkinsonism linked
to chromosome 17(FTDP-17)
Frontotemporal lobar degenerations (FTLD)
Pick’s disease (PiD)
Progressive supranuclear palsy (PSP)
Guadeloupean parkinsonism
Hemimegalencephaly (HME)
Neurodegeneration with brain iron accumulation
Prion protein cerebral amyloid angiopathy
Psychotic Alzheimer’ s disease
Creutzfeldt-Jakob disease (CJD)
Familial British dementia (FBD)
Familial Danish dementia (FDD)
Niemann-Pick disease, type C
defined by the accumulation of abnormal tau pro-
teins in the brain. The neuropathological phenotypes
distinguish themselves from each other according
to different tau morphological features (pretangles,
NFTs, threads, Pick bodies, dystrophic neuritis,
grains, and spherical cytoplasmic inclusions) and tau
isoforms (3R and 4R) [18].
3R and 4R tauopathies
Alzheimer’s disease
Alzheimer’s disease (AD) is the most prevalent
neurodegenerative disease associated with age-
related dementia. It is characterized by both A␤
extracellular plaques and intracellular neurofibril-
lary tangles made up of 3R and 4R tau [19, 20].
Pretangles are cytoplasmic tau immunoreactivity in
neurons without apparent formation of fibrillary
structures. In Alzheimer’s disease, such tau depo-
sition is considered to represent a premature state
prior to fibril formation (AD-pretangles), later to form
neurofibrillary tangles and finally ghost tangles. This
morphological evolution from pretangles to ghost
tangles is parallel with their profile shift from four
repeat (4R) tau-positive pretangles to three repeat
(3R) tau-positive ghost tangles with both positive
neurofibrillary tangles in between. This complemen-
tary shift of tau profile from 4R to 3R suggests that
these tau epitopes are represented interchangeably
along tangle evolution. The intracellular neurofibril-
lary tangles formed by abnormal tau proteins cause
deficits through a loss-of-function mechanism in AD
489
Table 1
Mutation associated with tau
haplotypes H1/H2
MAPT (S305S, S305I)
MAPT (N296H, N296N, P301L, P301S, S305N, G389R, R406W, N410H,
E10 + 16), H1 haplotype
MAPT (A152T, K257T, L266V, G272V, N279K, 280K, N296, K298E,
P301L, P301S, S305N, S305S, K317M, G335S, V337M, G389R, R406W,
E10 + 3, + 12, + 14, + 16) or progranulin
MAPT (G55R, I260V, L266V, G272V, N296H, P301S, P301T, L315R, S320F,
P332S, E342V, S356T, V363A, V363I, T427M)
MAPT (K257T, G272V, N279K, S305N, S320F, K369I, G389R)
MAPT (R5L, L284R, P301L, S305S, E10 + 14, + 16), H1 haplotype
H1 haplotype
AKT1, AKT3
PLA2G6
Codon 145 of PRNP
H2 allele of the extended MAPT haplotype
PRNP
ITM2B
ITM2B
NPC1, NPC2
[21]. Clinically, AD presents with typical and atyp-
ical manifestations including memory and learning
impairment, executive dysfunction, aphasia, visual,
practical problems, and mental symptoms in the late
of AD [22].
Primary age-related tauopathy
Primary age-related tauopathy (PART) replaces
these names (“tangle-predominant senile dementia”,
“tangle-only dementia”, “preferential development
of NFT without senile plaques”, and “senile demen-
tia of the neurofibrillary tangle type”) to describe the
neurofibrillary tangle pathology that is observed in
the brains of aged individuals [23]. In comparison
with AD, PART has an association with MAPT tau
H1 haplotype while having no genetic risk associated
with apolipoprotein gene (␧4) [24]. However, neu-
rofibrillary tangles in PART are made up of 3R and
4R tau as those in AD. Hence, it is difficult to dis-
tinguish AD and PART. The relation between PART
and AD is still not clear.
Chronic traumatic encephalopathy
Chronic traumatic encephalopathy (CTE) is a
progressive neurodegenerative disease caused by
repetitive head injuries [25]. The symptoms will
be present after a long period of latency. The
periods for different individuals vary from sev-
eral years to several decades. It classically presents
with mood, cognitive, and behavioral symptoms,
including depression, aggression, impulsivity, suici-
dal ideation, apathy, short-term memory loss, and
490 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
executive dysfunction [26]. The concept was first
introduced in 1927 [26], and the symptoms of CTE
was reported by Harrison Martland in 1928 [27].
Subsequently, hyperphosphorylated tau was found in
small cerebral vessels, cerebral sulci, periventricu-
lar areas, subpial regions, subcortical structures, and
brainstem nuclei and it also had an immune response
for both 3R and 4R tau [26]. Besides, the astrocytic
tau pathology was observed in periventricular and
subpial areas, and astrocytic tangles were formed in
CTE [25].
4R tauopathies
Corticobasal degeneration
Corticobasal degeneration (CBD) is related with
huge burden of tau inclusions in white matter, basal
ganglia and brainstem. It classically presents with
motor features (myoclonus, dystonia, gait abnor-
malities, bradykinesia, limb and axial rigidity) and
higher cortical features (cortical sensory loss, apha-
sia, apraxia, cognitive impairment, alien limb, and
behavioral changes) [28]. Some patients showed a
frontotemporal pattern of cognitive deficits (such as
personality change, a progressive non-fluent aphasia
and impaired awareness of deficit) and supranuclear
gaze palsy [29]. Besides these clinical symptoms,
behavioral changes and psychiatric symptoms with-
out motor symptoms were also found in CBD, but
less severe degenerative changes were found in the
substantia nigra and subthalamic nucleus of these
patients [30]. CBS, CBD-bvFTD, PSP syndrome, and
progressive non-fluent aphasia (PNFA) were 4 clin-
ical subtypes of CBD [31]. Patients with CBD and
Richardson syndrome have greater atrophy in anterior
corpus callosum, more severe neuronal loss in sub-
stantia nigra and less neuronal loss in the subthalamic
nucleus, when compared with PSP [32].
Progressive supranuclear palsy
PSP refers to Richardson’s syndrome or PSP
syndrome [33]. In 1964, Richardson’s syndrome
(PSP-RS) was first described by Steele, Richardson,
and Olszewski [34]. Early postural instability/falls,
supranuclear gaze palsy, variable cognitive impair-
ments, apraxia of speech and pseudobulbar affect
were also observed in patients [19]. Abnormal accu-
mulation of 4R-tau proteins was seen in PSP patients,
and they were present in different neuroanatomical
patterns to produce variable clinical features [33].
PSP variants are well-recognized in recent years and
include PSP-parkinsonism (PSP-P), PSP-CBS, pure
akinesia with gait freezing (PAGF), PSP-bvFTD, and
PNFA [35]. The cortical tau pathology was more
significant in PSP-CBS, PSP-bvFTD, and PNFA
than in PSP-P and PAGF. PSP-P and PAGF are
brainstem-predominant PSP syndromes. Compared
with PSP-RS, they showed more severe degeneration
and less cortical tau pathology in substantia nigra,
globus pallidus, and subthalamic nucleus [36].
Argyrophilic grain disease
Argyrophilic grain disease (AGD) is described
in amygdale, entorhinal cortex, hippocampus, and
neighboring temporal cortex in patients with adult
onset dementia and is characterized by spindle-
shaped “grains” [37]. In peri-amygdaloid white
matter and hippocampus, AGD presents with oligo-
dendroglial coiled bodies and pretangles [18].
Besides, tau pathology was found in different
regions in different stages. The changes in AGD
are dependent on tau neurofibrillary tangles, which
are biochemically difficult to distinguish from AD.
Cognitive decline, episodic memory loss, demen-
tia, personality changes, aphasia, emotional and
mood imbalance (irritability, delusions, amnesia,
apathy, irritability, dysphoria and agitation), promi-
nent abnormal behavior, and aggression have been
noted in the patients of AGD, but no specific clinical
syndrome was found to diagnose this disease [38].
3R tauopathies
Pick’s disease
PID is first used to describe atrophy of the
frontotemporal lobes in patients with behavioral dis-
turbances and progressive language disorder, now
used to describe the disease with tau-positive intra-
neuronal “Pick body” inclusions [39]. Clinically, it
presents with the disorder of social comportment,
executive impairments, PPA, visuospatial deficits
and akinetic-rigid syndrome with executive. The
clinical symptoms of PID were associated with
bvFTD, PPA, and CBS [40]. The autopsy found other
tauopathies including CBD, PSP, AGD, AD and TDP-
43 proteinopathies in bvFTD patients [41]. The poor
specificity of bvFTD for PID neuropathology neces-
sitated the recent clinical research criteria for bvFTD
in order to more accurately predict PID. The stud-
ies of PPA variants showed various results. Semantic
variant PPA (svPPA) and PNFA were present in dif-
ferent tauopathies. The former is due to TDP-43
proteinopathies and the latter is due to PSP and CBD.
The “Pick body” inclusions were mainly made up of
 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies 491

3R tau and distributed in hippocampus, dentate gyrus, Biomarkers of tau in neuroimaging

and cortical areas [42]. The pathogenesis of muta-
tions in tau proteins has been mentioned in FTDP-17.
Recent studies have developed a novel 3R mutant tau
transgenic model for better understanding the natural
history, progression and therapy of PiD [43]. More-
over, a novel missense mutation in E12 of MAPT
(p.Q336H) has been suggested to cause PiD, possibly
by increasing 3R tau isoforms aggregation [44].
BIOMARKERS OF TAUOPATHIES
A biomarker is a parameter which reflects the
progress of disease and the effects of treatment.
Recently, neuroimaging biomarkers of tauopathies
will provide strong underpinnings for prevention,
diagnosis, and therapeutic targeting.
Positron emission tomography (PET) may be one
of the noninvasive imaging technologies to measure
tauopathies and associated neurodegeneration in
the brain. PET imaging of tau pathology relies on
two major radioactive tracers: 18 F-labeled (t1/2 =
109.8 min) tracers and 11 C-labeled (t1/2 = 20.3 min)
tracers [45]. With the development of the PET trac-
ers, many tracers were reported to be applied to the
detection of tau pathology including 18 F-FDDNP,
18 F-THK523, 18 F-THK5117, 18 F-THK5105,
18 F-THK5351, 18 F-AV-1451(T807), 18 F-T808, 11 C-
PBB3, 11 C-THK951, lansoprazole, RO6931643,
RO6924963, and RO6958948 [3, 46–52]. The char-
acteristics of these tracers were described in Table 2.
A phase 0 trial of 18 F-FDDNP to evaluate tau values

Table 2
Tracers of PET imaging for tau
Tracers Affinity to tau Characteristics Reference
18 F-FDDNP Nanomolar affinity Non-selectivity for intercellular NFTs and extracellular [3]
A␤ plaques
18 F-THK523 High binding affinity and 12-fold Lower selectivity to PHF tau, in gray matter than white [46]
selectivity for tau than A␤ matter, not detected in non-AD tauopathies and
asynuclein deposits
18 F-THK5105 Higher binding affinity than 18 F-THK523 Relation with brain atrophy and dementia severity; a [47, 48]
relatively slower clearance from the brain and higher
lipophilicity; a lower signal to noise ratio
18 F-THK5117 Higher binding affinity than 18 F-THK523 Relation with brain atrophy and dementia severity [49]
Higher pharmacokinetics and better signal-to-noise
ratios than 18 F-THK5105
18 F-THK5351 high tau binding affinity in AD brains Higher signal-to-noise ratios, faster kinetic and lower [3]
white matter retention than 18 F-THK5105
and18 F-THK5117
18 F-AV-1451(T807) Higher nanomolar affinity and 25-fold Associated with diseases severity, distribution of [50]
selectivity for PHF tau over A␤ retention coincides with PHF tau and lower retention
in white matter; rapid washout, brain extraction and
no plasma metabolites entering the brain
18 F-T808 Higher nanomolar affinity and 25-fold The same function with18 F-T807 more rapid distribution [50]
selectivity for PHF tau over A␤ in the brain and maintain a steady state during the
scan, substantial defluorination phenomenon
11 C-PBB3 a 40–50 times higher affinity for NFTs Not only present in AD but in CBD and PSP and [49]
than for senile plaques candidate tracers were for tau but not A␤ and crossed
the blood–brain barrier
Lansoprazole Subnanomolar affinity to tau fibrils No entry into the brain but labeled with 11 C or18 F will [51]
entry into the brain without obstacles
11 C -THK951 slightly lower affinity to tau low lipophilicity, fast clearance and rapid brain uptake [52]
RO6931643, high-affinity binders on tau aggregates at Rapid brain entry, washout and safe metabolic patterns [52]
RO6924963 and the 3 H-T808 binding site and lack
RO6958948 affinity to A␤
18 F-FDDNP: 2-(1-(6-[(2-[18 F] fluoroethyl) (methyl) amino]-2- naphthyl) ethylidene) malononitrile; 18 F-THK523:2-(4-aminophenyl)-
6-(2-[18 F] fluoroethoxy) quinoline; 18 F-THK5105:6-[(3-[18 F] fluoro-2-hydroxy) propoxy]-2-(4-dimethylaminophenyl) quinolone;
18 F-THK5351:6-[(3-18 F -2-hydroxy) propoxy]-2-(4-methylaminopyridyl) quinoline; 18 F-T807: (E)-4-(2-(6-(2-(2-(2-[18 F] fluoroethoxy)

ethoxy) ethoxy) pyridin-3-yl) vinyl)-N-methyl benzenamine; 18 F-T808:2-(4-(2-[18 F] fluoroethyl) piperidin-1-yl) benzo (4, 5) imidazo (1, 2-a)
pyrimidine; 11 C-PBB3: a tau PET tracer constructed around a phenyl/pyridinyl-butadienyl-benzothiazole/ benzothiazolium (PBB) scaffold;
NFTs, neurofibrillary tangles; PHF, paired helical filaments; AD, Alzheimer’s disease; CBD, Corticobasal degeneration; PSP, Progressive
supranuclear palsy.
492 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
in Parkinson’s disease dementia has been completed,
but no results have been posted (https://clinicaltrials.
gov/ct2/show/NCT02243982). 13 clinical trials for
18 F-AV-1451 have been recruiting patients. Two trials
of 18 F-AV-1451 have been completed, but no results
are reported (https://clinicaltrials.gov/ct2/show/
NCT02079766 and https://clinicaltrials.gov/ct2/
show/NCT01992380). In the living human brain,
18 F-AV1451 makes it possible for the regional
distribution of tau pathology visually [53]. A phase
II trial for18 F-AV1451 to measure the distribution of
tau proteins in living human brain is ongoing (https://
clinicaltrials.gov/ct2/show/NCT02191267). At the
same time, 18 F-T807 is also in phase II process
as a diagnostic PET imaging tracer for AD and
neurodegeneration characterized by tau pathology
[54]. Besides, 18 FMNI-798 was used to evaluate
tau protein burden in AD in a phase I and II trial
(https://clinicaltrials.gov/ct2/show/NCT02640092]).
RO6931643, RO6924963, and RO6958948 as the
new tracers for PET are being tested in humans, and
a phase I trial has been completed to assess the ability
to detect tauopathy (https://www.clinicaltrials.gov/
ct2/show/NCT02187627).
Biomarkers of tau in cerebrospinal fluid
CSF tau species have been considered as the poten-
tial biomarkers for tauopathies, which are useful to
diagnose and identify different forms of neurodegen-
eration. Several researchers found that CSF t-tau and
p-tau have been considered as biomarkers for AD, and
the concentration of t-tau in AD has a two- to three-
fold increase than in controls, while the p-tau in CSF
shows a specificity of 80–100% [55]. Tau phospho-
rylation sites found in CSF up to now are Ser199,
Thr231, Thr 181, Ser 396/404, and Ser235 [55]. As
for p-tau181, it has low specificity and sensitivity to
distinguish AD and non-AD cases [56], and this abil-
ity increases after binding to A␤1-42 and t-tau [57].
The diagnostic power of A␤1-42 /p-tau181 is higher
than A␤1-42 and t-tau in the discrimination between
AD and FTD. When focusing on the discrimination
between AD and CJD, p-tau181P/T-tau shows signif-
icantly higher diagnostic power than A␤1-42 , t-tau,
and A␤1-42 /p-tau181P.
Besides AD, a reduced ratio of CSF p/t-tau has
been proved to have 82.4% positive predictive value
to detect TDP pathology in FTLD [58]. The levels
of the 20–22 kDa NH2-truncated form of human tau
in CSF could be rarely discovered in non-demented
cases, which could distinguish between cognitive
impairment patients and cognitively healthy subjects
influenced by heterogeneous neurological disorders
with a higher sensitivity of 85% and a low specificity
of 65% [59]. It is not a biomarker for the diagnosis
of cognitive impairment.
Biomarkers of tau in peripheral blood
Platelets are not only the main reserve of the
amyloid precursor protein, but include several tau
molecules. High molecular weight tau proteins were
detected in platelets of peripheral blood in AD
[60]. Tau fragments, tau-A and tau-C (a caspase-
3 cleaved tau fragment) are detected in serum,
which serve as the novel biomarker in serum for
the neurodegeneration [61–63]. Recent studies have
shown that plasma tau is not an AD biomarker
in individual people, and it just partly reflects AD
pathology [64]. The levels of tau proteins were sig-
nificantly increased in serumas indicators for severe
TBI and Olympic boxing [65]. Minor axonal dam-
age induced by punches causes the increase of
plasma tau. The plasma tau will significantly increase
after a bout in 1–6 days [65]. Circulating miR-
NAs also provide the evidence for AD. The serum
levels of cell-free miR-125b in serum decrease in
AD [66].
MECHANISMS OF TAUOPATHIES
Tau hyperphosphorylation
Phosphorylation plays the pivotal role in phys-
iological and pathological function of tau. In the
longest tau isoform, there are 85 potential sites of
phosphorylation–45 serines, 35 threonines and 5
tyrosines [67]. Among them almost 40 sites become
abnormal phosphorylated in tauopathies [68]. Phos-
phorylation sites in tau are in the C-terminal tail
region and proline-rich region [69]. Many factors
such as accelerated aging, traumatic brain injury
(TBI), LRRK2, hypothermia, ␤-N-methylamino-
L-alanine (BMAA), ischemia, oxidative stress,
methanol, and Cytoplasmic FMR1 interacting pro-
tein 2 (CYFIP2) induce hyperphosphorylation of tau
[70–75]. Among them, accelerated aging contributes
to an acceleration of tau hyperphosphorylation,
leading to the development of behavioral changes
which influence tau pathogenesis [75]. Recent stud-
ies indicated that tau phosphorylation is a risk factor
associated with the extent of cognitive impairment
due to TBI. Meanwhile, elevation of GSK-3␤ kinase
 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
activity and reduction in PP2A phosphatase activ-
ity have been suggested as, respectively, positive and
negative factors associated with the severity of TBI.
Altogether, these results suggest a role of tau phos-
phorylation pathway for the alterations of injured
neurons in mediating cognitive damages of TBI [76].
Tau phosphorylation is exquisitely sensitive to tem-
perature, increasing by 80% for each degree below
37◦ C, due to exponential decrease in PP2A activ-
ity during direct hypothermia, or anesthesia-induced
hypothermia [77]. BMAA leads to tau hyperphos-
phorylation by activating metabotropic glutamate
receptor 5 (mGluR5). Then, mGluR5 results in
the release of PP2Ac and its phosphorylation at
Tyr307 to inhibit PP2A [71]. Transient brain ischemia
has been shown to induce tau hyperphosphoryla-
tion. Recent studies confirmed that tau protein was
dephosphorylated during brain ischemia. In addition,
the activity of GSK-3␤ increased and the activity
of PP2A decreased. After reperfusion, tau protein
was hyperphosphorylated; the activity of GSK-3␤
decreased; the activity of PP2A remained low. Impor-
tantly, the interaction of tau with GSK-3␤ and
PP2A was altered during ischemia and reperfusion
[78, 79]. Methanol not only leads to acute neuro-
logical sequelae, including blindness and death, but
low concentrations of methanol also lead to hyper-
phosphorylation of tau and apoptosis of hippocampus
neurons [74]. The lack of CYFIP2 increases the
expression of alpha-calcium/calmodulin-dependent
kinase II in order to exacerbate tau hyperphospho-
rylation [80].
MicroRNAs (miRNAs) participate in the progress
of tau phosphorylation, such as miR-922, miR-125b,
and miR-132. MiR-922 induces tau phosphoryla-
tion through reducing the expression of ubiquitin
carboxy-terminal hydrolase L1 (UCHL1), and affects
tau phosphorylation through influencing the num-
bers of NFTS [81]. MiR-125b promotes tau
hyperphosphorylation by its overexpression. When
miR-125b was injected into mice, cdk5, p35, and
p44/42-MAPK signaling were upregulated and the
anti-apoptotic factor Bcl-W and the phosphatases
DUSP6 and PPP1CA were suppressed, leading to
tau phosphorylation [82]. MiR-132 loss promotes
tau pathology through regulating the expression of
inositol 1,4,5-trisphosphate 3-kinase B (ITPKB),
which regulates tau phosphorylation [83]. In the
Drosophila tauopathy model, proto-oncogenes sup-
presses tau-mediated neurodegenerative diseases
by reducing abnormal tau hyperphosphorylation
[84].
493
Tau aggregation
Tau is a highly soluble unfolded protein and not
aggregated with each other in physiological con-
ditions and concentrations. Tau aggregation is not
only the result of the phosphorylation, but also can
be affected by other factors. Negatively charged
molecules are the inducers of non-phosphorylated tau
aggregation [4], including heparin, anionic micelles,
RNA, synthetic particles, fatty acids, fatty acid-
like molecules (such as arachidonic acid), and lipid
vesicles. Heparin induces the polymerization of
tau fragments by binding to the second and third
microtubule-binding repeats [85], while arachidonic
acid is more effective than heparin in promoting
aggregation of full-length tau when the number
of K18, a tau fragment identified as one of the
four repeats of MBD, which is united to the
lipid bilayer, oversteps a critical surface density
[86, 87].
Acetylation of tau prevents degradation of phos-
phorylated tau, leading to tau aggregation [88]. In an
animal model of tauopathy, the insoluble tau frac-
tion was observed after the acetylation, suggesting
that acetylation promoted soluble tau to insoluble
tau in order to affect the process of aggregation
[89]. CREB binding protein (CBP) and p300 acety-
late different residues of tau, changing tau’s intrinsic
propensity to aggregate [90]. In addition to acetyl-
transferase, acetylation also regulates the process of
tau aggregation through other ways. At KXGS motifs,
acetylation and phosphorylation act in a competi-
tive relationship and are regulated by HDAC6 [90].
The inhibitors of HDAC6 facilitate tau acetylation
and prevent tau phosphorylation at these motifs to
interfere with tau aggregation propensity. In addi-
tion, HDAC6 could also impact on turnover of tau
through regulating the acetylation of its substrate
Hsp90, suggesting combination treatment of HDAC6
and Hsp90 inhibitors as a potent therapeutic treatment
for diseases with accumulation of tau [91]. Recently,
ac-K174 has a critical role in tau accumulation and
toxicity. Besides, the acetyl-mimic mutant K174Q
inhibits tau degradation and promotes tau aggrega-
tion [92]. Recent studies suggest that stress granules
(SG) are a form of pathology associated with neu-
rodegenerative diseases. SG proteins, such as TIA-1
and TTP, bind to phosphorylated tau, and that binding
increases with the severity of the disease. Meanwhile,
SG proteins might contribute to generating tau pathol-
ogy, perhaps by creating local environments with high
concentrations of phospho-tau [93]. Latest studies
494 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
suggest that the pathological tau aggregation may
be initiated through the regulated self-assembly of
core SG-associated RNA binding proteins, such as
TIA-1 [94].
Additionally, truncation at both ends (N-terminal
or C-terminal) of the tau molecule could confer a
toxic gain of toxic function. The in vivo model of
tauopathy based on the truncated tau protein clearly
shows that truncation is a “productive” modifica-
tion that can initiate tau neurofibrillary degeneration
[95]. The truncated forms of tau protein are espe-
cially found in PHFs, suggesting that tau truncation
might contribute to tau aggregation [96]. Recent stud-
ies suggest that there is a complex interaction between
phosphorylated and truncated tau species [97]. More-
over, tau truncation could modulate tau spreading.
Finally, changes in tau 3R/4R ratio may result in
differences in microtubule stability.
Neurotoxicity of tau oligomers
As mentioned above, hyperphosphorylation of tau
consists of neurofibrillary tangles (NFT). Before the
formation of NFT, tau forms two intermediate forms
of NFT: tau oligomers, not discovered by atomic
force microscopy (AFM), and granular tau oligomers,
detected by AFM [1]. Tau oligomers play a cru-
cial role in neurodegeneration, synaptic dysfunction
and mitochondrial loss. Tau oligomers impair mem-
ory by disrupting anterograde memory storage when
researchers inject the monomers of full-length recom-
binant p-tau-441 or fibrils into the C57BL/6 wild mice
hippocampus [98]. Recent animal studies found that
mice expressing TauC3 (a caspase-cleaved form of
tau) showed memory and learning impairment and
the decrease of synaptic number at early stage accom-
panied with tau oligomer formation [99].
Tau oligomers cause synaptic dysfunction through
affecting the density of presynaptic and neuronal traf-
ficking and also cause mitochondrial dysfunction by
activating caspase-9 [98]. Intracellular p-tau accu-
mulation causes mitophagy deficits, which inserts
into the mitochondrial membrane to activate the
membrane potential and to cause the decrease
of PTEN-induced kinase 1/Parkin. PTEN-induced
kinase 1/Parkin reduces p-tau-induced impairment
[100]. Except these, miR-219 targeting tau synthe-
sis directly causes the toxicity of tau [101]. Recently,
a new mechanism of tau toxicity is found to con-
tribute to glial activity impairment in AD and other
tauopathies, which induces microtubule bundling and
activate the Rho-GTPase-ROCK pathway [102].
Mechanism of autophagy-lysosome system
in tauopathies
Autophagy is a catabolic system which can degrade
abnormal proteins, lipids and organelles through
lysosomes. It plays an important role in cell home-
ostasis and keeps the metabolic balance between
synthesis and degradation and subsequent turnover
of cytoplasmic materials in a stressful environment.
Autophagy is classified into three types: microau-
tophagy, chaperone-mediated autophagy (CMA) and
macroautophagy [103, 104]. Many factors inhibit
autophagy which leads to tau accumulation in neu-
rodegenerative diseases, including mTOR, p53 tumor
suppressor, cAMP, NH4Cl, cathepsin inhibitors,
3-methyladenine, chloroquine, Bcl-2, Bcl-XL, and
increased concentration of Ca2+ in cytoplasm which
comes from the endoplasmic reticulum [105–108].
The mTOR is a primordial inhibitory signal which
participates in the initial process of signal transduc-
tion. When growth factors such as insulin-like growth
factor bind to insulin-like growth factor receptors
(IGF1R), class I PT3K pathway, which catalyzes the
conversion of PIP2 to PIP3, is activated. PIP3 recruits
AKt and DDK1 to membrane, allowing the latter one
to phosphorylate AKt. The active AKt inhibits the
activity of the TSC1/TSC2 complex, whose activ-
ity can lead to an overall inhibition of mTORC1
signaling. By contrast, intracellular signals include
nutrient starvation, low energy levels (increase of the
AMP/ATP ratio), hypoxia, and DNA damage inhibit
mTOR activity [109]. CMA (chaperone-mediated
autophagy) may generate tau fragment aggregation
[110]. There are two CMA-targeting motifs in MBDs
of tau, 336QVEVK340 and 347KDRVQ351, which
participate in the transportation of tau to lysosomal
membranes. The overexpression of neuronal PAS
domain protein 4 promotes the clearance of patholog-
ical tau by inducing autophagy [111] and provides a
novel therapeutic approach to tauopathies.
Mechanism of ubiquitin-proteasome system
in tauopathies
Like autophagy-lysosome system, the ubiquitin-
proteasome system (UPS) is a primary mechanism
of organism that mediates the degradation of abnor-
mal or misfolded proteins and short-live proteins.
The system contains two parts–ubiquitination and
proteasome, which interact with each other to medi-
ate the degradation of abnormal tau [112]. In the
brain in AD, polyubiquitin chain of PHF-tau is
 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
found, which is attached to others through four lysine
residues (Lys63, Lys48, Lys11, and Lys6) [106].
The affinity between tau and microtubule is reduced
when tau is modified with ubiquitination. Meanwhile,
researchers found that E3 ubiquitin ligase activity
played a role in the ubiquitination of tau [113]. E3
ubiquitin ligase determines the specificity of interac-
tion between ubiquitin and substrates.
Some inhibitors of proteasome, lactacystin, epox-
omicin, MG132, and leupeptin put the degradation
of abnormal tau off. TNF-␣/NF␬B reduces 26S
proteasome and then decreases the activity of pro-
teasome by S5b/PSMD5 pathway, which plays a
vital role in UPS-associated tauopathies [114]. Not
only in AD, but in transient cerebral ischemia, pro-
teasome dysfunction causes E10 exclusion of tau
and a decrease of Tra2␤, leading to the imbalance
of 4R/3R and neurodegeneration [115]. UBB + 1
interacted with polyubiquitin chains to inhibit the
degradation of polyubiquitinated substrate through
26S proteasome, a dose-dependent inhibitor of pro-
teasome [116]. Maintained stability and activity of
UPS is a potential therapy for neurodegenerative
diseases and tauopathies.
Propagation of tauopathies
Preclinical phase of the disease, mild cognitive
impairment and severe dementia are three stages of
clinical symptoms of AD. Each stage has two sequen-
tial neuropathological stages according to Braak
stages (stage I-II, stages III–IV, stages V–VI) and
approximate three stages described by Delacourte
(Delacourte stages 1–3, Delacourte stages 4–6 and
Delacourte stages 7–10) [3, 117]. The six or ten
sequential neuropathological stages reveal the prop-
agation of tau pathology, but the precise process of
tau propagation is still a mystery.
Release of tau
The appearance of extracellular tau tangles is iden-
tified at stage III, and how tau is released is crucial
for us to understand the process of extracellular tau
tangle formation. Extracellular tau is not only from
the dying neurons but also from other unconven-
tional pathways [118]. Calcium affects the release of
endogenous tau by an unconventional pathway [119].
However, the concentration of calcium also influ-
ences the process of endogenous tau secretion. The
release of tau is increased when the agonist S-AMPA
increases the activity of glutamate receptors [120].
The pre-synaptic compartment consists of abundant
495
tau, released tau, and tau fragments via the pattern of
potassium-induced depolarization [121, 122].
Endocytosis spreading pathway
Extracellular tau not only can aggregate tangles
in interstitial fluid and CSF, but also can be inter-
nalized via endocytosis. Uptake of tau fibrils occurs
through adsorptive endocytosis, which is time- and
temperature-dependent [123]. Another endocytosis
may occur when extracellular tau interacts with
receptors, which is activated by intracellular calcium
via M1/M3 muscarinic receptor stimulation [124].
Meanwhile, the interaction between tau and mus-
carinic receptors generates toxic influences and leads
to the release of tau into the extracellular space and
neuron death [125]. Other mechanisms have been
identified, including the entry of non-fibrillar and sol-
uble tau aggregates via dynamin-driven endocytosis
[126] and proteoglycan-mediated macropinocytosis.
Except abnormal tau, PBS-soluble phosphorylated
high-molecular-weight tau takes part in tau prop-
agation and is present in the form of endogenous
tau [127].
Trans-synaptic spreading pathway
Synapses play a crucial role in the spreading
of tauopathy. Studies of human postmortem tissue
roughly described the anatomical distribution of the
tauopathies, and demonstrated that these pathology
areas were linked by synapses [117]. Furthermore, in
vivo studies revealed that tau pathology was propa-
gated to other areas associated with synapses from
the initial location [128]. How the precise process
of propagation happened is still uncertain, except
trans-synaptic and endocytosis spreading. Tau may
be transferred through tunneling nanotubes between
cells and membrane penetration [129]. Besides, new
research in animal models showed that microglia
and exosomes promoted tau propagation in the
mammalian brain and revealed that microglia could
transfer tau to other neurons [130]. Recently, an
animal model showed that amyloid promoted tau
propagation and increased the toxicity of tau [131].
POTENTIAL HYPOTHESIS MECHANISM
Although above-mentioned mechanisms can cause
tauopathies in their own ways, many evidences from
animal’s experiments, preclinical models and post-
mortem research show that the mechanisms interact
with each other to cause tauopathy (Fig. 2). Abnor-
mal tau proteins are mainly degraded through two
496 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies

Fig. 2. Mechanisms of tauopathies. In the brain, the mutations of genetic (①) and the disorder of splicing (②) induce the production
of abnormal tau proteins. Abnormal tau proteins detach from microtubule, leading to the instability of microtubule and the damage of
axon transport. Meanwhile, the imbalance of protein kinases and phosphatases and other factors can induce tau hyperphosphorylation (③).
Abnormal tau proteins and hyperphosphorylated tau aggregate with each other, non-phosphorylated tau also aggregate after interacting
with negatively charged molecules (④). The primary form of aggregation is tau oligomers and cause mitochondrial (⑤), then tau oligomers
polymerize to form NFTs (⑥) and cause tauopathies. The UPS (⑦) and autophagy-lysosome system (⑧), mediated abnormal tau degradation,
are blocked by the inhibitors, causing the increase of abnormal tau levels. Intracellular tau secretes to extracellular space via targeting to
special receptors (a), exosomes (b), and with the help of microglia (c). These abnormal tau pass to next neuron through endocytosis (f), trans-
synaptic pathway (d), or exosomes (e), resulting in new pathology. MTs, microtubules; NFTs, neurofibrillary tangles; DUBs, deubiquitinating
enzymes; 3MA, 3-methyladenine; CMA, chaperone-mediated autophagy; UPS, ubiquitin proteasome system.

systems–UPS and autophagy-lysosome system. Tau
proteins induce neuron death and neurodegeneration
by a series of processes including hyperphosphoryla-
tion, aggregation, oligomers, and then the formation
of the NFTs. The NFTs are made up of paired helical
filaments (PHFs) and straight filaments, which are
composed of abnormal tau proteins. Subsequently,
abnormal tau in extracellular space propagates via
endocytosis and trans-synaptic pathway and causes
the damage of neighboring neurons, leading to the
tauopathies.
EXPERIMENTAL ANIMAL MODELS
OF TAUOPATHIES
Experimental animal models of tauopathies serve
as efficient systems for interpreting the role of
abnormal tau in the neurodegeneration and the exper-
iments of treatment. Some crucial aspects of human
tauopathies have been recapitulated in modified ani-
mals including Caenorhabditis elegans, Drosophila,
and especially mouse models (Table 3) (see review in
[132]). Caenorhabditis elegans and Drosophila are
two easy tools for genetic studies. The Caenorhab-
ditis elegans models have revealed tau toxicity,
axonopathy, motor dysfunction, and early death
[133]. This model is also used to study drug screen-
ing [134]. The Drosophila models are used to identify
several pathological pathways or susceptibility genes.
Besides, these models profit from low redundancy of
the genome and low consumption [135].
The first transgenic mouse models of human
tauopathies were produced by only expressing spe-
cific human tau isoforms (4R/2N) [136]. These
models exhibited hyperphosphorylated tau and pre-
tangle tauopathy, and NFTs were not observed in
 Table 3
The major transgenic mouse models of tauopathies
Mutation Promoters DNF initiation Histopathology Phenotype
G272V(4R2N) MoPrP ND Tau filament formation, transgene expression in oligodendrocytes and neurons No obvious neurological deficits
N279K(4R0N) MoPrP ND Phosphorylated tau in the olfactory bulb, hippocampus, cerebellum, Impairment in acquisition of spatial learning
diencephalons, brain stem and cerebral cortex and active avoidance, motor deficit and
cognitive decline
N279K(4R2N) hTau 13 months hence the 4R:3R ratio, tau protein accumulation in neurons and tufted astrocytes The degeneration of the nigrostriatal
dopaminergic pathway, motor and
behavioral deficits
P301L(4R0N) CaMK-II 1 months NFTs, neuronal loss Cognitive impairment and motor deficit
P301L(4R0N) MoPrP ND Neuronal loss, Age- and dose-dependent NFTs development, neurogenic muscle Motor and behavioral impairment, premature
atrophy death
P301L(4R0N) neuropsintTA 3 months Hyperphosphorylated tau, PHF1, insoluble tau aggregated, axonal degeneration ND
P301L(4R1N) 2 3 -CNP 3–9 months Impaired axonal transport, the disruption of myelin and axons preceding Progressive motor weakness and weight loss,
filamentous oligodendroglial tau inclusions probably a consequence of neurogenic
muscle atrophy
P301L(4R1N) GFAP 12–24 months Insoluble tau, age-dependent accumulation of tau inclusions in astrocytes Motor deficits and additional deficits in
neuromuscular strength
P301L(4R2N) mThy-1 6–7 months Tau hyperphosphorylation, widespread NFTs, no axonopathy Late minor motor phenotype, muscle and
tissue wasting, cognitive decline
P301L(4R2N) mThy-1.2 3 months NFT-like, insoluble, short filament structures with hyperphosphorylated tau gliosis Cognitive decline
P301L(4R2N) MoPrP 2–8 months age- and gene-dose-dependent development of NFT, insoluble tau, axonal motor and behavioral deficits
spheroids, anterior horn cell loss and axonal degeneration, Pick-body-like
neuronal lesions
P301S(4R0N) mThy-1.2 5–6 months Abundant filamentous tau in spinal cord and brain stem Motor deficits and cognitive decline,
behavioral abnormalities
P301S(4R1N) MoPrP 3–6 months Early synaptic pathology, neuronal loss, NFTs formation Motor deficits and cognitive decline, limb
weakness, progressing to paralysis
V337M(4R2N) PDGF␤ 11 months Neuronal cell death, PHF, degenerating hippocampal neurons Cognitive deficits, decreased hippocampal
neural activity
V337M(3R2N) mThy-1 12 months Insoluble tau, filamentous neurofibrillary tangles in the brain, aberrantly Cognitive decline
phosphorylated tau
R406W(4R2N) MoPrP 12 months Tau lesion with advancing age in neuronal perikarya, insoluble tau, tangles Motor deficits
C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies

formation
R406W(4R2N) CaMK-II 14–18 months Hyperphosphorylated tau, insoluble tau filament in aged mice only, tangles Cognitive decline, no obvious sensorimotor
formation deficit
R406W(4R2N) Syrian hamster PrP 10 months Hyperphosphorylated, insoluble tau starting to aggregated in amygdala and Motor deficit and cognitive decline
hippocampus
G272V/P301S mThy-1.2 3–6 months NFTs, ghost tangles Behavioral abnormalities, cognitive decline
(4R1N)
G272V/P301L/ mThy-1 ND Insoluble filament and tangles formation ND
R406W(4R2N)
ND, not determined; Ref, reference; MoPrP, mouse prion protein promoter; CaMK-II, Ca 2 + /calmodulin kinase II; NFTs, neurofibrillary tangles; PHF1, paired helical filaments 1; 2 3 -CNP,
2 ,3 -cyclic nucleotide 3 -phosphodiesterase; GFAP, glial fibrillary acidic protein; PDGF␤, platelet-derived growth factor␤.
497
498 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies

these models. To observe the NFTs, novel models
were generated [132]. Meanwhile, the relationship
between neuronal loss and neurofibrillary pathology
was also found. Not only did the transgenic (tg)
mice models of P301L demonstrate the process of
tauopathies in neuronal and glial, but G272V, N279K,
P301S, V337M, and R406W were created to explore
the function of tau in tauopathies [132]. These mod-
els exhibited different aspects and initiation time of
tauopathy. Subsequently, the double mutant (K257T
and P301L, G272V and P301S) and triple mutant
(G272V, P301L, and R406W) have been reported to
test pathogenic hypotheses of tauopathy and thera-
peutic strategies [137, 138]. In the future work, more
available models for human tauopathies should be
produced.
TARGETING TAU THERAPEUTICS IN
TAUOPATHIES
Most tau-targeted therapies (Fig. 3) are growing
at a rapid pace due to the discovery of the vital role
of tau in neurodegeneration. Some drugs used in the
treatment of tauopathies have been put into clinical
phase II or III trials (Table 4), and at the same time
new drugs continue to be discovered.
Targeting phosphorylation in tauopathies
As a hallmark in AD and other neurodegenera-
tive diseases, abnormal tau phosphorylation has the
indelible effects on the process of pathology and
diseases. The protein kinases provide a vital target
site for tau phosphorylation, especially glycogen syn-
thase kinase 3 (GSK-3). A number of GSK-3 kinase
inhibitors, such as lithium, valproate, escitalopram,
and tideglusib, decrease tau phosphorylation and alle-
viate the process of diseases [139–142]. Currently,
some of these drugs have been put into the clinical
trials to assess the pharmacokinetics and discharge
excretions. The information is provided in Table 4.
No clinical benefits have been found in a phase II
clinical trials for valproate in AD [143]. Escitalo-
pram reduces the levels of tau hyperphosphorylation,
which are induced by A␤1-42 through the pathway
of Akt/GSK-3␤ [144]. Other tau protein kinases are
inhibited for prevention of tau phosphorylation, but
no tau protein kinases inhibitors except GSK-3 have
been applied to clinical trials until now. To develop
other kinases inhibitors and to apply those to clini-
cal trials provide a new direction for the treatment of
tauopathy, but the safety and efficacy of drugs should
be taken seriously.

Fig. 3. Targeting tau-based therapeutics for tauopathies. The therapeutics of tauopathies consist of targeting phosphorylation, targeting
aggregation, increasing microtubule stabilization, tau immunization, clearance of tau, anti-inflammatory treatment, and other therapeutics.
MT, microtubule; PelA, peloruside A; NAP, daventide; NSAID, non-steroidal anti-inflammatory drugs.
 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies 499

Table 4
Drugs of tauopathies for clinical trials
Drugs Clinical Targeting diseases ClinicalTrials.gov Conditions
phase Identifier
Lithium II PSP, CBD, AD NCT00703677 Completed
NCT01055392 Not verified
II AD NCT00088387 Completed
Valproic acid II PSP NCT00385710 Completed
0 AD NCT01729598 Completed
Tideglusib II AD NCT01350362 Discontinued
Metformin II AD NCT01965756 Ongoing
Memantine II HD, PDD, DLB NCT01458470 Completed
NCT00630500 Completed
II ALS NCT01020331 Completed
III FTD NCT00594737 Completed
IV AD NCT00800709 Completed
IV AD NCT00551161 Completed
NCT00933608* Completed
LMTX (TRx0237) III AD NCT01689233 Ongoing
III AD NCT01689246 Completed
III bvFTD NCT01626378 Completed
BMS-241027 I AD NCT01492374 Completed
NAP II PSP, CBD, FTDP-17 NCT01056965 Ongoing
AADvac1 I AD NCT01850238 Completed
I AD NCT02031198 Ongoing
II AD NCT02579252 Ongoing
C2N-8E12 I PSP NCT02494024 Ongoing
BMS-986168 I PSP NCT02460094 Ongoing
I PSP NCT02658916 Ongoing
TPI-287 I PSP, CBD NCT02133846 Ongoing
I AD NCT01966666 Ongoing
LMTX, leuo-methylthioninium; AD, Alzheimer’s disease; CBD, Corticobasal degeneration; HD,
Huntington’s disease; PDD, Parkinson’s disease dementia; PSP, Progressive supranuclear palsy;
FTD, Frontotemporal dementia; FTDP-17, Frontotemporal dementia and parkinsonism linked
to chromosome 17; NA, not available; bvFTD, Behavioral variant frontotemporal dementia.
*It includes preclinical phase.

The activation of PP2A also supplies a direction
for reducing tau phosphorylation. Sodium selenate,
phosphotyrosyl phosphatase activator, memantine
and metformin reduce tau phosphorylation through
elevating the activity of PP2A [145–147]. Memantine
has been applied in clinic to attenuate the symptoms
of AD. Currently, folic acid reduces tau phosphory-
lation via inhibiting PP2A demethylation reactions
[148]. The methylation of DNA and protein plays a
key role in regulating the activity of phosphatase and
the inhibition of methylation will be of tremendous
value in the treatment of tauopathies.
Targeting aggregation in tauopathies
To inhibit or reverse tau aggregation becomes
one of the great therapeutic strategies for neu-
rodegeneration. Some small molecule inhibitors are
demonstrated to inhibit and disassemble tau aggrega-
tion, such as rhodanines, phenylthiazol-hydrazides,
anthraquinones, benzothiazoles, phenothiazines, and
so on [139, 149]. Methylene blue is testified to
decrease the levels of tau in ex vivo slice cultures
from transgenic mice of tauopathy [150]. The pos-
itive results have been found in a phase II trial of
methylene blue [151]. However, the National Toxi-
cology Program used rodents to show that long-term
usage of methylene blue resulted in some malig-
nancies and lymphomas within the intestines, so
leuco-methylthioninium (LMTX) is developed in
AD and FTD which are more bioavailable and less
toxic than MTC [152]. At present, LMTX is being
applied in several phase III studies in AD and bvFTD,
the clinical effects will be achieved in early 2016
[151]. Recent animal studies found that anle138b
reduced tau aggregation, ameliorated disease symp-
toms, improved cognition, and increased survival
time of tau transgenic PS19 mice [153].
Natural products have also shown the function
of anti-aggregation, such as oleuropein agly-
cone, hydroxytyrosol, oleuropein, and grape seed
polyphenolic [154, 155]. Recently, O-GlcNAc, one
modification of tau, is demonstrated to reduce the
aggregation propensity of tau [156]. The above-
500 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
mentioned inhibitors can prevent tau aggregation or
disassemble tau aggregation, but we still need much
work to do before these strategies are applied in clinic.
Increasing microtubule stabilization
in tauopathies
Hyperphosphorylated and polymeric forms of tau
result in a reduction of microtubule stability, and
this reveals that keeping the stability of microtubule
is one therapeutic strategy for tauopathies. Pacli-
taxel, peloruside A, Epothilone D, NAP (davuentide),
BMS-241027 and TPI-287 improve axonal function,
MT density, and cognitive performance [157–159].
Paclitaxel is not appropriate for human tauopathies
treatment because of the poor blood–brain bar-
rier permeability, while Epothilone D permeates the
blood–brain barrier. The compound makes some
improvements in a phase II clinical trial and has
no serious effects on patients with mild to moderate
AD [160].
Immunization strategies for tauopathies
Active immunization
Active immunization of tau pathology decreases
the levels of aggregated tau through the func-
tions of tau antigen. The phosphoepitopes of tau
are demonstrated to reduce the levels of accumu-
lated tau and prevent the process of tau related
pathology via inducing the active immunization,
such as a PHF1 phosphoepitope in P301L trans-
genic mouse, phosphorylated epitope S422(PS422),
pS396/pS404, pS231, pS212/pS214, pS202/pT205,
and AADvac1 [161–164]. A phase I trial is under-
way for pS396/pS404 by AC Immune and Janssen
and other information has been reported about this
trial [165]. Tau antigen not only induces active immu-
nization, but carries a risk of causing autoimmunity
and related tauopathy.
Passive immunization
Not only active immunization, but passive immu-
nization has an effect on the treatment of tau pathology.
These antibodies consist of anti-tau antibodies, AT8,
three monoclonal antibodies of tau, MC31, DA31,
HJ9.3, HJ9.4, PHF1, PHF13, PHF6, anti-pSer413
antibody, MAb86 and C2N-8E12 [166–174]. Except
these, a novel antibody-DC8E8 is found to dis-
tinguish mis-disordered tau with physiological tau,
and it inhibits the interaction between pathological
tau, which reduces tau oligomers and neurofibril-
lary pathologies in animal models [175]. Recently,
a new therapeutic strategy for passive immunization
is found to prevent phospho-tau pathology by using
encapsulated cell implants to transmit recombinant
anti-amyloid-␤ antibodies to protect against the mis-
folded proteins [176]. Studies on tau antibodies still
need to explore therapeutic development.
Clearance of tau in tauopathies
Targeting autophagy-lysosome system
Autophagy-lysosomal system degrades the levels
of abnormal tau. Therefore, enhancing the activity
of autophagy and inhibiting the degradation of lyso-
some will be efficient to promote the degradation of
tau and alleviate neurodegeneration. Rapamycin and
temsirolimus elevate the activity of autophagy and
reduce abnormal tau in the mouse model of tauopa-
thy via targeting the mTOR pathway [177, 178].
Besides the mTOR pathway, other drugs also induce
autophagy via targeting the process of autophagy-
lysosome formation, such as trehalose, methylene
blue, lithium, sodium valproic, carbamazepine, and
sulforaphane [150, 179–183]. The development of
autophagy-lysosome activators that can elevate clear-
ance of pathological tau without negative effects will
be of immense therapeutic value for tauopathies and
other proteinopathies.
Targeting ubiquitin-proteasome system
It becomes difficult to clear aggregated proteins
after the dysfunction of UPS. The enhancement of
ubiquitin-proteasome activity promotes the process
of tau degradation. Rolipram promotes proteasome
activity. IU1, a deubiquitinating enzyme related to
proteasome, puts proteasomal degradation off [184,
185]. CHIP, carboxy-terminus of heat shock protein
70-interacting protein, interacts with phosphorylated
tau firstly. Then it transfers phosphorylated tau to
proteasome when heat shock protein 90 captures the
abnormal tau [186]. Besides, cAMP promotes degra-
dation of misfolded proteins by increasing the activity
of 26S proteasome through PKA and Rpn6 [187].
These two pathways interact with 19s subunit to
affect the activity of proteasome. Maybe, increasing
the levels of cAMP will be a useful way of treating
tauopathies.
Anti-inflammatory treatments in tauopathies
Neuroinflammation plays a vital role in the
process of AD and other related tauopathies.
 C.-C. Tan et al. / Tauopathies: Mechanisms and Therapeutic Strategies
Microglial activation promotes the expression of
pro-inflammatory cytokines and leads to tau hyper-
phosphorylation and neuronal death [188]. In
tauP301L mice deficient in CX3CR1 receptor,
microglia are over-expressed and tau is hyperphos-
phorylated [189], thus leading to the aggregation
of tau and related tauopathies through two path-
ways. One is related to the activity of p38 MAP
kinase [190], another is related to the increased
NRF2-ARE (nuclear factor (erythroid-derived 2)-like
2-antioxidant response element) activity to inhibit
the overactivation of microglia [189]. So, targeting
CX3CL1-CX3CR1 and/or neuronal IL-1 receptor-
p38 and NRF2-ARE signaling pathway is a valid
therapeutic strategy for tauopathies. Recent studies
find that SCM-198 (Leonurine) inhibits the overacti-
vation of microglia via NF-␬B and c-Jun N-terminal
kinase pathways [191]. Besides, immunosuppressant
FK506 reduces tau aggregation and the expression of
microglia. The immunophilin FKBP52 (a member of
FK506-binding protein family) directly interacts with
hyperphosphorylated tau to inhibit the aggregation of
tau [192].
CONCLUSION AND OUTLOOKS
Tauopathies are morphologically, biochemically,
and clinically heterogeneous neurodegenerative dis-
eases defined by the accumulation of abnormal tau
proteins in the brain. Although the development of
various studies, medicine, and technology has helped
interpret many vital aspects of the tauopathies, more
effective treatments for tauopathies still need to be
explored. Efforts to discover imaging markers with
the characteristics of lower toxicity, higher kinetics,
and greater permeability across the blood brain bar-
rier should be continued and combined with more
efficient approaches to be applied in clinical tri-
als. Given the central role of tau in tauopathies,
many treatments have constantly emerged, includ-
ing targeting phosphorylation, targeting aggregation,
increasing microtubule stabilization, tau immuniza-
tion, clearance of tau, anti-inflammatory treatment,
and other therapeutics. It still has a long way to go
before we obtain a drug therapy targeting multifactor
mechanisms.
ACKNOWLEDGMENTS
This work was supported by grants from
the National Key R&D Program of China
501
(2016YFC1305803), the National Natural Sci-
ence Foundation of China (81471309, 81371406,
81571245, and 81501103), the Shandong Provin-
cial Outstanding Medical Academic Professional
Program, Taishan Scholars Program of Shan-
dong Province (ts201511109, tsqn20161078, and
tsqn20161079), Qingdao Key Health Discipline
Development Fund, Qingdao Outstanding Health
Professional Development Fund, and Shandong
Provincial Collaborative Innovation Center for
Neurodegenerative Disorders, Research Award Fund
for Outstanding Young and Middle-aged Scientists
of Shandong Province (BS2015SW006), Projects
of medical and health technology development
program in Shandong province (2015WSA02054).
Authors’ disclosures available online (http://
j-alz.com/manuscript-disclosures/17-0187r1).
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