Pathological Changes of Tau Related to Alzheimer's Disease - ACS

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Pathological Changes of Tau Related to Alzheimer’s Disease Dandan Chu, and Fei Liu ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00457 • Publication Date (Web): 11 Oct 2018 Downloaded from http://pubs.acs.org on October 15, 2018

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ACS Chemical Neuroscience

Pathological Changes of Tau Related to Alzheimer’s Disease Dandan Chua and Fei Liub,*

aKey

Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China,

Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PR China bDepartment

of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State

Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA

*Corresponding author: Address: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA. Tel: 718-494-5263; Fax: 718-494-1080. [email protected].

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Abstract Alzheimer’s disease (AD), the most common form of dementia, is characterized by extracellular -amyloid plaques (A) and intracellular neurofibrillary tangles (NFTs), which are considered as major targets for AD therapies. However, no effective therapy is available to cure or prevent the progression of AD up till now. Accumulation of NFTs, which consist of abnormally hyperphosphorylated tau, is directly correlated with the degree of dementia in AD patients. Emerging evidence indicates that the prion-like seeding and spreading of tau pathology may be the key driver of AD. In the past decades, greater understanding of tau pathway reveals new targets for the development of specific therapies. Here, we review the recent research progress in the mechanism underlying tau pathology in AD, and briefly introduce tau-based therapeutics.

Keywords tau pathology, Alzheimer’s disease, hyperphosphorylation, truncation, aggregation, propagation

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1. Introduction Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by progressive memory loss combined with problems with language and orientation, changes in mood, loss of motivation, difficulty with self-care, and impairments in thinking and behavior 1. AD is believed to be a contributor of 60-70% of dementia cases 1. The primary risk for AD is aging. Most forms of AD are sporadic, usually starting at age ~ 65 and progressing slowly over 7-10 years 2. Less than 1% of all cases are early onset familial AD, which is inherited in an autosomal dominant manner and develops similar symptoms as sporadic AD prior to age 65. Mutations of the genes for APP (amyloid precursor protein), PSEN1 (presenilin 1) and PSEN2 (presenilin 2) are responsible for the presence of familial AD 3. AD symptoms are associated with progressive loss of neurons and synapses in multiple brain regions, especially in the frontal cortex and hippocampus. The two major neuropathological hallmarks of AD are the extracellular amyloid plaques (A) and the intracellular neurofibrillary tangles (NFTs), which contain paired helical filaments (PHFs) of abnormally hyperphosphorylated tau

4-5.

In the past decades, therapies targeting Aβ did not show effective

benefit in clinical trials, casting doubt on the amyloid hypothesis of AD 6-9. The number of NFTs rather than A plaques, is positively correlated with the severity of dementia in AD patients 10. NFTs pathology is initiated in the locus coeruleus and transentorhinal area, from where it progresses to the limbic system and further to the isocortex - the Braak stages

11

- whereas the

distribution of NFTs correlates with the progression of the disease 12. Recent studies showed that tau pathology can be induced in the injection sites and anatomically connected brain regions by injection of tau aggregates isolated from AD brains or produced in vitro by incubating recombinant tau with polyanionic heparin

13-17,

similar to steps in propagation of the tau

pathology seen in AD, introducing the concept of “propagation of tau pathology”. Increasing evidence suggests that prion-like propagation of tau pathology contributes to AD progression 18,

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providing potential novel therapeutic strategies 7. In this review, we will discuss recent developments in tau biology and advances in tau pathological changes related to AD, and briefly introduce tau-based drug discovery.

2. Structure and function of tau Gene expression of tau Tau is one of the major microtubule-associated proteins in the brain. Human tau is encoded by the microtubule-associated protein tau (MAPT) gene, located on chromosome 17q21.31. MAPT consists of 16 exons. In the brain, the alternative splicing of exons 2, 3, and 10 produces six isoforms of tau containing zero (0N), one (1N) or two (2N) N-terminal inserts and three (3R-tau) or four (4R-tau) C-terminal microtubule-binding repeats (Fig. 1)

19.

The longest isoform of tau

consists of 441 amino acids (2N4R, tau441) with molecular weight of 45.85 kDa. The expression of tau isoforms is developmentally regulated. The fetal human brain expresses only the shortest isoform of tau (0N3R, tau352), whereas adult human brain expresses all six isoforms with approximately equal levels of 3R-tau and 4R-tau

19-20.

Rodent tau shows about 90% homology

with human tau. 3R-tau is only expressed in fetal and newborn rodents, whereas 4R-tau is mainly expressed in adult rodents 20-21. Alternative splicing of pre-mRNA is regulated by the interaction of trans-acting factors with the cis-elements. There are major two groups of trans-acting factors, serine and arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs)

22.

Tau pre-mRNA contains

many cis-elements, including a SC35-like splicing enhancer, a polypurine enhancer (PPE) and an A/C-rich enhancer (ACE) at the 5’ end, and an exonic splicing silencer (ESS) and an exonic splicing enhancer (ESE) at the 3’ end of tau exon 10, and an intronic splicing modulator (ISM) and an intronic splicing silencer (ISS) at 5’ end of intron 10. Mutations in these cis-elements could alter the expression of tau exon 10, causing several neurodegenerative diseases 23. Splicing factors bind to these elements, and suppress exon 10 inclusion [SRSF3 (SRp20)

24,

SRSF4

(SRp75) 25, SRSF7 (9G8) 26, SRSF11 (SRp54) 27, U2AF, PTB and hnRNP G 28] or promote exon 10 inclusion [hTRA2-beta1, CELF3, CELF428-29, SRSF1 (ASF/SF2)

30,

SRSF2 (SC35)

31,

4


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SRSR6 (SRp55)

32,

protein 4 (RBM4)

30].

SRSF9 (SRp30c) 34,

RNA helicase p68 (DDX5)

and Tar DNA-binding protein 43 (TDP-43)

35

33,

RNA binding motif

promote tau exon 10

inclusion. The function of these splicing factors is modulated by phosphorylation by kinases including SR protein kinase (SRPK) (TOP1)

37,

36,

cdc-like kinase (CLK/Sty)

cAMP-dependent protein kinase (PKA)

and regulated kinase 1A (DYRK1A)

31, 39,

38,

36,

DNA topoisomerase I

dual-specificity tyrosine-phosphorylated

glycogen synthase kinase-3β (GSK-3β) 40, and AKT

serine/threonine kinase (AKT) 41. Due to the limitation of conventional PCR, studies about the amount of tau isoform transcripts in AD brain have been contradictory patients were not found in many cases reported in some studies

45, 48.

42-45.

42-44, 46-47,

Alterations of 4R-tau/3R-tau ratio in AD

while increases in 4R-tau transcripts were

Some new approaches have also been employed to analyze the

levels of tau isoform transcripts in AD. For instance, a microarray analysis of RNA isolated from single-tangle-bearing neurons detected decreased 3R-tau transcripts in AD patients

49.

Another

group used the polony profiling method to quantify individual tau isoforms, and found that a 1.3-fold increase in 4R-tau and 35% reduction in 3R-tau transcripts in AD. Among the six isoforms, 0N4R particularly accounted for the increase, while 2N3R and 1N3R were significantly decreased in AD cases

50.

The changes of protein levels of tau isoforms are more

complicated in AD. 4R-tau and 3R-tau appear equally in the early-stage and some cases of end stage AD

51-52.

In several cases of late-stage AD, 3R-tau protein is predominantly expressed in

specific brain regions with many extracellular neurofibrillary tangles (NFTs), including the subiculum, CA1 and entorhinal cortex 46, 52. These results imply that dysregulation of tau exon 10 splicing could be associated with AD progression rather than initiation. Notably, along with others, we have shown that expression of tau isoforms and total tau varies in different regions in rodent and human brains, which may cause differential vulnerability/resistance of brain regions to tau pathology 44, 53-54. So

far,

107

tau

mutations

have

been

identified

in

human

(https://www.alzforum.org/mutations). Fifteen of these mutations are associated with AD, while

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others are correlated to Frontotemporal dementia (FTD), Parkinsonism linked to chromosome 17 (FTDP-17), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and other tauopathies. Tau mutations alter the peptide sequence or/and trigger the imbalance between 4R-tau and 3R-tau by changing alternative splicing 55.

Protein structure of tau Tau is an intrinsically disordered protein, which consists of many serine/threonine, proline and arginine/lysine/histidine residues, making it a highly water-soluble and basic protein with little secondary structure, and easily hyperphosphorylated. The longest isoform of human tau (tau441) contains four domains, a N-terminal projection domain which projects way from the microtubule surface, a proline-rich region responsible for the interaction of proteins with SH3 domains, a microtubule-binding domain which is involved in promoting tubulin assembly and tau aggregation, and a C-terminus (Fig. 1 and Fig. 2A)

56-57.

Tau protein is post-translationally

modified in multiple ways including phosphorylation, truncation, glycosylation, glycation, ubiquitination, nitration, methylation, lipoperoxidation, sumoylation, and acetylation

58

(Table.

1). Dysregulation of tau post-translational modifications is involved in the etiology of AD and other tauopathies.

Functions of tau Tau binds at the interface between tubulin heterodimers through its microtubule-binding repeats thereby stabilizing microtubules in vitro 59. 4R-tau isoforms have a greater affinity than 3R-tau isoforms, and are more efficient at promoting microtubule assembly 60. In normal fetal neurons, tau is enriched on dynamic microtubules in the distal axon elongation of the labile domain of microtubules

63.

55, 61-62,

where it enables the

In AD brain, pathological tau would detach

from microtubules, leaving them sensitive to severing proteins like katanin, resulting in a dramatic loss of microtubule mass 64.

6


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Additionally, tau can regulate intracellular transport along the axon

65-66.

In physiological

conditions, little tau is detected in dendrites, where it is involved in modulating postsynaptic receptor activity

67-68.

Tau is also found in the nucleus, most likely to protect the integrity of

DNA in stress response

69.

Lastly, tau is expressed at low levels in oligodendrocytes and

astrocytes. However, neuronal tau pathology is predominant in AD 70.

3. Pathological changes of tau The intracellular neurofibrillary tangle composed of abnormally hyperphosphorylated tau is one of the two neuropathological hallmarks of AD. The tau pathology starts in the coeruleus/subcoeruleus complex and the transentorhinal area (Braak stages I and II), gradually progresses toward the limbic system (Braak stages III and IV) and eventually the isocortex (Braak stages V and VI) 71. The topographic expansion of tau pathology is highly correlated with the cognitive impairment characteristics in AD, and has been used to classify the disease into six consecutive Braak stages 11.

Hyperphosphorylation of tau Tau is a phosphoprotein. The longest brain tau isoform, tau441, contains 80 serine/threonine and 5 tyrosine residues that can potentially be phosphorylated. At least 40 serine/threonine and 2 tyrosine phosphorylation sites have been identified in PHF. Normal brain tau contains 2–3 mol phosphate/mole of the protein. In AD brain, however, the phosphorylation levels of tau are 2-3-fold increased

58.

Various abnormally phosphorylated sites of tau are found in AD brain,

including Thr181, Ser195, Ser198, Ser199, Ser202, Thr205, Thr212, Ser214, Thr217, Thr231, Ser235, Ser262, Ser353, Ser396, Ser400, Ser404, Ser409 and Ser422 7. Abnormal hyperphosphorylation of tau is the key step in tau pathogenicity in AD and other tauopathies

58.

According to the phosphorylation state and solubility, tau in AD brain can be

separated into three pools: non-hyperphosphorylated functional tau (AD-tau), abnormally

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hyperphosphorylated tau (AD P-tau), and tau aggregated into insoluble PHFs (PHF-tau)

72.

Normal tau protein has a “paper clip” structure, in which the N- and C-terminal ends fold over the

microtubule-binding

domain

to

prevent

the

protein

from

73.

self-aggregation

Hyperphosphorylation of tau changes the protein charge and conformation, exposes the microtubule-binding domain, thereby leading to tau self-oligomerization and aggregation

58.

Approximately 40% of AD P-tau forms cytosolic oligomers that sedimented at 200,000×g 72. The major function of normal tau is to promote microtubule assembly 60. Unlike normal tau, AD P-tau can sequester normal tau as well as other microtubule-associated proteins like MAP1 and MAP2, thus disrupting microtubule assembly. However, PHF-tau has no effect on microtubule assembly, suggesting that tau oligomers and not fibrillar aggregates are cytotoxic. Dephosphorylation of AD P-tau with protein phosphatases restores tau biological activity towards microtubule assembly in vitro and diminishes tau pathology in vivo, further indicating that hyperphosphorylation is crucial in tau pathology

74-76.

In addition to effects on microtubule

stability, hyperphosphorylation of tau may influence the protein sorting, degradation, truncation, and aggregation 55. Tau

is

phosphorylated

by

proline-directed

protein

kinases

such

as

GSK-3β,

cyclin-dependent-like kinase-5 (CDK5), DYRK1A, and non-proline-directed protein kinases such as calcium/calmodulin activated protein kinase II (CaMKII), protein kinase A (PKA), casein kinase 1 (CK1), and microtubule affinity-regulated kinase 110 (MARK p110) in vivo. In AD brain, the activities or expression of these kinases are significantly altered

58, 77-83.

Tau

dephosphorylation is mediated by protein phosphatases, especially protein phosphatases 2A (PP2A), which accounts for over 70% of tau phosphatase activity in the human brain 84. In AD brain, the total tau phosphatase activity is reduced to half, which also contributes to the abnormal hyperphosphorylation of tau

84.

Therefore, the imbalance between tau kinase and phosphatase

activities is suggested to be the origin of tau hyperphosphorylation 85.

8


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Glycosylation of tau Glycosylation is an enzymatic process that covalently attaches oligosaccharides to the side chain of

a

protein.

Several

kinds

of

oligosaccharide,

including

galactose,

mannose,

N-acetylglucosamine, and sialic acid are reported to modify tau in human brain 86. Normally, tau is not modified by classic glycosylation, but is O-GlcNAcylated (with monosaccharide -N-acetylglucosamine attached to the hydroxyl groups of serine or threonine residues)

87.

However, tau from AD brain is aberrantly glycosylated through N-linkage (with glycans attached to the amide group of the asparagines residues) 86, 88. Aberrant glycosylation of tau may precede its hyperphosphorylation in AD brain, and seem to facilitate tau phosphorylation.89. In contrast, O-GlcNAcylation of tau, which negatively regulates tau phosphorylation by competing for phosphorylation sites on the protein, was decreased in AD brain 87.

Acetylation of tau Tau is acetylated by the histone acetyltransferase p300 (EP300) or CREB-binding protein (CBP), and deacetylated by sirtuin 1 (SIRT1) and histone deacetylase 6 (HDAC6) at more than twenty Lys residues within the microtubule-binding repeats and the flanking region possesses intrinsic acetyltransferase activity that allows auto-acetylation

93.

90-92.

Tau also

Acetylated-tau

pathology differs depending on the modification sites. For instance, high levels of acetylated tau at Lys163, Lys174 and Lys180 are detected in mild to moderate stages AD brains, preceding hyperphosphorylation of tau and NFT formation. Acetylation at these sites could inhibit the degradation of hyperphosphorylated tau, thus contribute to phosphorylated tau accumulation. Moreover, acetylation at Lys274, Lys280, Lys281 and Lys369 are found to impair tau function, and up-regulated in AD brain 90-91, 94-96. By contrast, Lys259, Lys290, Lys321 and Lys353 within the KXGS motifs are normally acetylated to prevent tau phosphorylation and aggregation, and are hypoacetylated in AD brain 97.

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Ubiquitination of tau As a natively unfolded protein, normal tau degradation could be catalyzed through an ATP/ubiquitin-independent pathway

98.

Nevertheless, tau is ubiquitylated by various ubiquitin

ligases (E3 ligases) including the C-terminus of the Hsc70-interacting protein (CHIP), TNF receptor-associated factor 6 (TRAF6) and axotrophin/MARCH7

99-101.

Mass spectrometry

reveals that soluble PHF-tau isolated from AD brains is ubiquitinated at microtubule binding domain at residues Lys254, Lys311 and Lys353

102.

Some of these residues are competitively

methylated or acetylated in AD brain 103. Tau hyperphosphorylation and N-terminal cleavage are shown to facilitate ubiquitylation of tau neurofibrillary tangle formation of tau inclusions

106-107.

104-105,

which might promote the

PHFs from AD brain are mainly monoubiquitylated rather

than polyubiquitylated, making it insufficient to induce the ubiquitin-proteasome system (UPS)-mediated proteolysis of tau aggregates

103.

Thus, enhancing polyubiquitylation and

degradation of tau might be a potential target for tau pathology 108.

SUMOylation of tau Tau can be post-translationally regulated by small ubiquitin-like modifier protein (SUMO), which is transferred to the side chain of lysine residues in a manner similar to ubiquitylation. Lys340 is the major sumoylation site of tau

109.

Sumoylation reciprocally stimulates tau

hyperphosphorylation at Tyr231 and Ser262, and inhibits tau ubiquitylation and degradation. SUMO-1 colocalizes with phosphorylated tau in AD brain and in amyloid plaques of amyloid precursor protein (APP) transgenic mice

110-111.

However, the relevance between sumoylation

and tau pathology in AD brain requires further investigation.

Glycation of tau Glycation is a nonspecific reaction of sugars and proteins, in which increased concentration of reducing sugars, generally glucose, are non-enzymatically linked to the terminal amino groups

10


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on the side chain of lysine residues. Glycation is detected in PHF-tau but not soluble tau purified from AD brains

112-113.

Glycation of tau mainly occurs in the microtubule binding domain, and

reduces its binding to microtubules, thus indirectly assists tau hyperphosphorylation and aggregation

113-115.

However, glycation alone is not sufficient to induce tau aggregation in vitro

116.

Nitration of tau Tau can be nitrated on four Tyr residues, Tyr18, Tyr29, Tyr197 and Tyr394. Nitration of all the four residues is found in AD brain; whereas Tyr197 nitration is also detected in normal brain, implying a physiological function

117-118.

Nitration of Tyr residues influences tau assembly in a

site-specific manner. Selective nitration of Tyr29 and Tyr197 increases the average length of tau filaments, whereas nitration of residues Tyr18 and Tyr394 decreases that in vitro

119.

Nevertheless, the roles of tau nitration in pathological conditions have not been extensively understood.

Truncation of tau As an intrinsically disordered protein (also known as a natively unfolded protein), tau is sensitive to protease digestion. Tau can be cleaved by calpain as well as other proteases both in vitro and in vivo

120.

Truncations of tau disrupt the “paper clip” structure of the protein and increase its

propensity to form aggregates, which can further nucleate the aggregation of normal full-length tau 55, 121. In AD brain, at least three site-specific cleavages of tau (Asn368, Glu391, and Asp421) have been identified in NFTs, and are correlated with the progression of Braak stages Similar truncations are also found in different mouse models of tauopathy

55.

122-124.

Unlike the

C-terminal truncation in NFTs, N-terminal truncations are found more associated with hyperphosphorylated high molecular weight tau oligomers (HMW-tau)

125.

Evidence has shown

that tau truncation alone is sufficient to induce hyperphosphorylation and aggregates

126.

Tau

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truncation can also induce toxic response like apoptosis which is independent of its function on aggregates 127. Thus, tau truncation plays a vital role in tau pathology.

Tau aggregation The natively unfolded tau monomers usually have random coil structure showing little tendency to form aggregates

128.

Partially folded forms of tau have less random coils but more -sheet

structures, which are required for the interaction between tau monomers 129-130. Two hexapeptide motifs of tau, 275VQIINK280 at the beginning of microtubule-binding repeat 2 and 306VQIVYK311 at the beginning of repeat 3, show propensity to undergo the conformational switch to -sheet structure that is responsible for the formation of aggregates

131-132.

Conversion of tau monomer

from an inert to a seed-competent form could initiate tau pathological aggregation

133.

Once the

partially folded conformation of tau monomer is triggered, they may successively aggregate together to form dimmers, soluble oligomers, insoluble PHFs and eventually NTFs 129, 134 (Fig. 2). When tau aggregates into PHFs, the repeat domains that contains β-sheet structures form the core of PHFs, while the N- and C-terminal domains contribute to a ‘fuzzy coat’ surrounding the filament core

123.

Aggregation of tau into PHFs and NFTs have been found in AD and other

related neurodegenerative diseases 135. All six isoforms of tau are detected in AD PHFs 18. Truncation and hyperphosphorylation are two major post-translational modifications that influence tau aggregation. Truncation of tau exposed the microtubule-binding repeats which are more likely to form aggregates hyperphosphorylation and aggregates

136-137.

Tau truncation alone is sufficient to induce

126, 136.

However, hyperphosphorylation of full-length tau

alone is not sufficient to induce the formation of insoluble aggregation. Only in combination with truncation could hyperphosphorylation induce tau aggregates

138.

Tau phosphorylation at

several sites (such as Thr231, Ser235, and Ser262) flanking the microtubule-binding repeats inhibits microtubule assembly and promotes its assembly into PHF hyperphosphorylation

might

facilitate

tau

aggregation

in

several

7,

139.

Generally,

ways.

Firstly,

12


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hyperphosphorylated tau detaches from microtubules, and may provide more free protein for aggregation 126. Secondly, hyperphosphorylated tau is able to sequester more normal tau into the aggregates in a prion-like manner

140.

Thirdly, hyperphosphorylation may alter tau degradation

and truncation, which indirectly affect tau aggregation 141-143. Some tau mutations affect its aggregation process. Missense mutations identified in frontotemporal dementia (FTD) and FTDP-17, including G272V, P301L, V337M and R406W, are more favorable substrate for hyperphosphorylation and are prone to form aggregates 144-145.

140,

Another example is the repeat-domain deletion mutation ΔK280 found in FTD. This

single amino acid deletion strongly reduces tau affinity for microtubules and promotes tau fibrillization by strengthening β-sheet structures 132, 145. Dysregulation of tau alternative splicing may also lead to tau aggregation. 4R-tau, which contains an extra microtubule-binding repeat, is more readily to bind and promote microtubule assembly than 3R-tau

146,

and could trigger more heparin-induced polymerization than the

combination of 3R-tau and 4R-tau do in vitro

147.

Increased 4R-tau/3R-tau ratio induces tau

phosphorylation and oligomerization in human tau-expressing mice model

148,

suggesting that

appropriate balance of 4R-tau and 3R-tau is important to prevent abnormal fibrillization. In addition, some co-factors containing strong negative charges (heparin, dextran sulfate, arachidonic acid and RNA) can induce tau aggregation in vitro

149.

For example, polyanions

(heparan sulfate) that compensate for excess positive charges of tau could cause a conformational switch of tau to form -sheet structures that facilitate aggregation

150.

Certain

proteins like 14-3-3ζ and FKBP4 are shown to induce aggregation of tau in vitro, possibly through stabilizing the aggregation-prone structure

55, 151.

Undigested products of mitochondrial

turnover may also trigger aggregation by facilitating the conformational change of tau 152.

Seeding and spreading of tau pathology Transcellular propagation of tau aggregates may drive the stereotyped progression of AD in a

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Page 14 of 45

prion-like manner that proteopathic tau seeds are transferred from a “donor cell” to a “recipient cell” where the seeds transform normal tau into aggregates (new seeds). Once formed in the coeruleus/subcoeruleus complex, tau seeds spread along the synaptically connected neurons to target large-scale human brain networks

18, 149

(Fig. 2). However, tau pathological propagation

follows a stereotypical pattern, implying differential vulnerability of brain regions to tau pathology 54. Tau seeds isolated from AD brain (AD P-tau) mice like P301L or P301S

13, 16,

76, 153,

extracted from tau transgenic

or artificially synthesized from microtubule-binding repeats of

human tau 154 can induce propagation of tau pathology in rodent brain. Spreading of tau pathology includes the following steps: 1) uptake of tau seeds, 2) templated tau aggregation, 3) secretion and 4) transcellular transfer of tau seeds 149. Uptake of tau seeds are mediated via clathrin-independent endocytosis and macropinocytosis involving heparan sulfate proteoglycans (HSPGs) or APP in vitro

155-158.

Dynamin, actin, Cdc42, and PI3K are shown

required for the internalization of tau seeds 155. Tau seeds from diverse sources display different uptake ability. Compared to species isolated from tau transgenic mice brain or assembled from recombinant tau, the soluble HMW-tau derived from AD brain is more efficiently internalized 15. The endosomal-lysosomal and autophagy pathways are involved in the clearance of tau aggregates

152.

Due to the age-related dysfunction of these processes159 or other unknown

mechanisms, internalized tau seeds escape from endosomal vesicles and are exposed to cytoplasm, where they may template the assembly of cytoplasmic tau via direct protein-protein contact

18, 154-155.

The danger receptor galectin-8 that monitors endomembrane integrity could

protect against the release of tau seeds by recruiting NDP52-dependent autophagy machinery 155. Although tau does not contain signal peptides, it is secreted in a monomeric and/or truncated non-phosphorylated form in physiological conditions

149.

Yet the mechanism and function of

neuronal tau release are not well understood. Assembled tau aggregates are released from cells through direct leakage from the presynaptic membrane vesicles

163-164

160,

exocytosis

or direct translocation across the plasma membrane

161,

exosome

165.

162,

synaptic

Tau truncation and

14


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hyperphosphorylation favor its secretion

165-166.

Increased neuronal activity is also shown to

stimulate tau release in vitro and promote tau propagation in vivo 167. The released tau aggregates are taken up by postsynaptic neurons and subsequently template new seeds formation. Recent reports show that microglia take up both soluble and insoluble tau168. Reactive microglia is sufficient to drive tau pathology in a cell-autonomous manner 169, and may promote the spreading of tau pathology through exosome-dependent secretion

170.

These results indicate

that microglia-mediated neuroinflammation could be one possible cause for the propagation of tau pathology.

4. Tau-based therapeutics To date, only five prescription drugs are approved by the US Food and Drug Administration (FDA) for the treatment of AD. Three of these drugs (donepezil, galantamine and rivastigmine) are cholinesterase inhibitors that prevent the breakdown of acetylcholine in the brain. The fourth drug, memantine, is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. The fifth medication is a combination of extended-release donepezil and memantine. However, the improvement of symptoms is limited, and none of these medications prevents or slows down the progression of AD. Based on the mechanisms underlying tau pathological changes in AD, new approaches aiming at inhibiting tau pathology have been developed recently (Table. 2).

Suppression of tau gene expression Since tau is a key molecule in AD pathology, and tau knockout induces no overt phenotype except for motor and cognitive deficits in aged mice, reduction of tau expression could be a potential strategy for AD prevention 171-172. Reducing endogenous tau levels has shown to protect against A-induced cognitive impairments and behavioral abnormalities in AD model mice

173.

Antisense oligonucleotides targeting of tau diminishes neuronal hyperexcitability in drug induced mice model of seizures

174.

In AD brain, several microRNAs like miR-219, miR-125b,

15



Page 16 of 45

miR-106b, and miR-132/122 have been found to regulate tau expression and phosphorylation 175-178.

However, whether inhibition of tau expression could be beneficial in AD treatment

requires more investigation.

Inhibition of tau phosphorylation Hyperphosphorylation

determines

the

spread

of

tau

pathology.

Inhibition

of

tau

hyperphosphorylation has long been considered as a therapeutic approach, and can be accomplished through modulating the balance between tau protein kinases and phosphatases. Tau is phosphorylated by kinases such as GSK-3, CDK5, PKA and CaMKII, nevertheless, inhibition of GSK-3 or CDK5 failed in Phase II clinical trials. PP2A, the main phosphatase of tau, mediates tau dephosphorylation both directly and indirectly by regulating the phosphorylation of tau kinases. Stimulating PP2A activity shows beneficial effects on cognitive deficit in AD model rats and patients. Several medications targeting PP2A activity are currently under development or evaluation in clinical trials 7. However, we recently found that GSK-3 enhanced the methylation and activity of PP2Ac and PP2A also dephosphorylates GSK-3 at Ser9 and enhanced its kinase activity

179.

Thus, GSK-3 and PP2A regulate each other and

control tau phosphorylation both directly and indirectly through each other. Targeting either of them may affect another and attenuate its role.

Inhibition of tau aggregation Tau aggregation inhibitor therapy aims at preventing the prion-like propagation of tau pathology. Derivatives of methylene blue have been shown to disaggregate tau filaments and tangles and prevent cognition impairment in tau transgenic mice

180.

However, benefits of these drugs (such

as methylene blue, Rember TM, and LMTX) are limited in human so far. For instance, LMTX, a second-generation tau aggregation inhibitor, failed to improve cognitive and functional skills in mild to moderate AD patients in Phase III trials 7. Recently, an aggregation inhibitor NPT088 has

16


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shown to lower A plaque and phosphor-tau pathology, and to improve cognitive performance in transgenic mice

181.

NPT088 is a fusion protein that combines the backbone of a human

immunoglobulin with a general amyloid interaction motif (GAIM) which recognizes and remodels multiple misfolded proteins including both A and tau. NPT088 is currently in phase I trials. Another approach to suppress tau aggregation is to disturb the steric zippers formed by the hexapeptides.

This structure-based design of non-natural amino-acid inhibitors of tau

aggregation might have therapeutic potential as well 182.

Microtubule stabilizers In AD brain, pathological tau detaches from microtubules leading to the disruption of microtubules. Stabilization of microtubule is thus considered as a potential therapeutic approach to make up tau-induced neurotoxicity. Microtubule stabilizers were initially designed to block cancer cell mitosis because they can bind to tubulin and disturb microtubule dynamics, block mitosis in the G2/M phase, and eventually induce programmed cell apoptosis 183. Whether these promising anticancer compounds show therapeutic effects in AD treatment still requires further evaluation 7.

Immunotherapy Although the mechanism remains unclear, tau immunotherapy, either active or passive, has shown to reduce tau pathology and improve cognitive performance in tau transgenic mice and rats. Tau-based active immunotherapy which induces natural immune response achieves more persistent antibody titer levels, but might raise the risk of autoimmune reaction and other disadvantages

184.

Two vaccines, AADvac-1 which against tau peptide aa 294-305 and ACI-35

which against phosphorylated tau peptide are now in Phase II and Phase I clinical trials respectively. AADvac-1, the first active tau immunotherapy candidate tried in human, induces antibodies with high affinity to truncated tau (tau151-391). AADvac-1 active immunotherapy 17



Page 18 of 45

reduces the levels of tau oligomers and AD-like tau hyperphosphorylation, diminishes the extent of neurofibrillary pathology, and improves behavioral phenotype in transgenic rat model

185.

Although induces some side effects, AADvac-1 vaccine has a favorable safety profile and induces immune response in mild to moderate AD patients

186.

ACI-35 is a liposome-based

vaccine that carries a synthetic phosphorylated peptide to mimic phosphorylated tau at residues Ser396/Ser404. ACI-35 treatment improves the clinical phenotype and reduces tau pathology in P301L tau transgenic mice 187. However, the clinical effectiveness and safety of these vaccines in AD patients require further investigation. Compared to active immunotherapy, the passive immunotherapy is a short-term immunization achieved by continuous injection of antibody, which can be designed highly specific to target epitopes regardless of the immune variation between patients. Antibodies are generated against hyperphosphorylated tau (RO6926496, RO7105705)

188,

conformations of tau (anti-tau oligomer-specific antibody) 189-190, fragments of tau (BMS-986168, C2N-8E12)

191,

and total tau (ABBV-8E12)

192.

The therapeutic values of these antibodies are

now tested in clinical trials 7. Notably, some of these antibodies like BMS-986168, C2N-8E12 and ASN120290 might be potential therapeutic agents for other tauopathies such as progressive supranuclear palsy (PSP)

193.

We recently reported that passive immunization with tau

antibody 43D (targeting tau 6-18) decreases both tau and A pathologies and improved cognition in 3xTg-AD mice, suggesting a potential therapy for AD and related tauopathies 194-196. However, passive tau-based immunotherapy faces several challenges, one of which is the blood-brain-barrier (BBB) that allows only 0.1-0.2% of circulating antibodies to the brain. Thus technologies designed to enhance antibody delivery into the brain should also receive attentions 197.

5. Conclusions and perspectives It has been over 30 years since tau was first found to be abnormally phosphorylated in PHF in

18


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1986

4-5.

Intensive research of the protein has revealed that tau undergoes many pathological

changes in AD brain, mainly including hyperphosphorylation, truncation, aggregation, seeding and spreading. Recent studies suggest that tau oligomers, rather than fibrillar aggregates, are the cytotoxic species that disrupt synaptic function, leading to neuronal death and the propagation of tau pathology

160, 198-200.

Thus, detection and clearance of toxic tau oligomers or

even the seed-competent monomers, before the formation of PHFs and NFTs at early stages of AD, could be of crucial importance in preventing tau pathology.

Acknowledgement This work was supported in part by funds from Nantong University, New York State Office for People Developmental Disabilities and the Neural Regeneration Co-innovation Center of Jiangsu Province and by grants from the National Natural Science Foundation of China (81300978) and U.S. Alzheimer’s Association (DSAD-15-363172).

19



Table 1. Post-translational modifications of human tau441. Modification (ref) Sites 201 Phosphorylation T17, Y18, Y29, T39, S46, T50, T52, S56, T69, T95, T102, T123, S131, T135, S137, T149, T153, T169, T181, S184, S195, S198, S199, S202, T205, S208, T212, S214, T217, T220, T231, S235, S237, S238, T245, S258, S262, T263, S285, S289, S293, S305, S341, S352, S356, T361, T373, T386, Y394, S396, T403, S404, S409, S412, S413, T414, S416, S422, S435 O-GlcNAcylation202203

Page 20 of 45

T101, T175, S210, S241, S324, S400, S433,

T123, S208, S238, S400, S409/S412/S413*

Acetylation103

K148, K150, K163, K174, K180, K224, K225, K234, K240, K254, K257, K259, K267, K274, K280, K281, K290, K294, K298, K311, K317, K321, K331, K343, K347, K353, K369, K370, K383, K385, K395

Ubiquitination103

K254, K259, K267, K281, K290, K298, K311, K317, K321, K331, K343, K347, K353, K369, K375, K385

SUMOylation109-110

K340

Glycation103

K67, K87, K132, K148, K150, K163, K174, K180, K190, K225, K234, K259, K267, K274, K280, K281, K290, K298, K311, K317, K321, K331, K340, K343, K347, K353, K369, K370, K375, K383, K385, K395

Nitration118

Y18, Y29, Y197, Y394

Methylation103

K24, K44, K67, K87, R126, K148, K150, R155, K163, K174, K180, K190, K234, K240, K254, K259, K267, K281, K290, K311, K317, K331, R349, K353, K369, K370, K375, K385, K395 * O-GlcNAcylation may occur on any of the three sites 202.

20


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Table 2. Tau-based therapeutic approaches. Approach

Name of Agent

Target type

Phase

Sponsor

Suppression of tau expression

IONIS-MAPTRx

Tau antisense oligonucleotide

1/2

Ionis Pharmaceuticals, Inc.

Inhibition of tau hyperphosphorylation

Insulin (Humulin® R U-100)

Insulin signaling activator

2/3

University of Southern California


Lithium carbonate

GSK-3 inhibitor

4

Ariel Gildengers


Metformin

Insulin sensitizer

2

University of Pennsylvania


Nicotinamide

Histone deacetylase inhibitor

2

University of California, Irvine


Nilotinb

Abl tyrosine kinase inhibitor

2

Georgetown University


Vorinostat

Histone deacetylase inhibitor

1

German Center for Neurodegenerative Diseases

Inhibition of tau aggregation

Methylene blue

Tau aggregation inhibitor

2

Peter Fox


NPT088

Tau/A aggregation inhibitor

1

Proclara Biosciences, Inc.


TRx0237

Tau aggregation inhibitor

Microtubule stabilizer

BMS-241027


1

Bristol-Myers Squibb


TPI-287


1

University of California, San Francisco

Active immunization

AADvac 1

Synthetic tau peptide derived from a.a. 294-305

1

Axon Neuroscience SE

Active immunization

ACI-35

Synthetic phosphorylated tau peptide at S396/404

1

AC Immune SA, Janssen

Passive immunization

ABBV-8E12

Anti-tau antibody

II

AbbVie


BIIB076

Anti-tau antibody

1

Biogen


BMS-986168

Anti-tau antibody

2

Biogen


JNJ-63733657

Anti-tau antibody

1

Janssen Research & Development, LLC


LY3303560

Anti-tau antibody

2

Eli Lilly and Company


RO7105705

Passive immunization against pS409

2

Genentech, Inc.

2/3

TauRx Therapeutics Ltd

21



Page 22 of 45

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Figure 1: Gene expression of human MAPT and protein structure of tau isoforms. Human MAPT gene locates on chromosome 17 and comprises 16 exons. Exon 0 and exon 1 encode the 5' untranslated region of MAPT mRNA, while exon 14 is transcribed into part of the 3' untranslated region. Exons 4a, 6, and 8 are expressed only in peripheral tissues. Alternative splicing of exons 2 (green, encodes N1) and 3 (yellow, encodes N2) produces tau isoforms with zero (0N), one (1N) or two (2N) N-terminal inserts of 29-amino acids each. Exons 9-12 encode microtubule-binding repeats (R1, R3 and R4 in blue, R2 in red). Alternative splicing of exon 10 (red, encodes R2) produces isoforms containing four (4R-tau) or three (3R-tau) microtubule-binding repeats.

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Figure 2. Structure and function of physiological and pathological tau. (A) Tau is natively unfolded (inert monomer, blue) in normal neurons. The major function of tau is to stabilize microtubules through the microtubule-binding domain (blue boxes). (B) In the diseased neurons from AD brain, post-translational modifications of tau, especially truncation and hyperphosphorylation, facilitate the detachment of pathological tau from microtubules, resulting in depolymerization of microtubules. Conformational change of tau converts the inert monomer into a seed-competent form (red), which may template the aggregation of larger assemblies, including dimers, oligomers, and finally PHFs. (C) Seed-competent monomers and aggregates transport from one neuron to another via multiple pathways. Internalized tau seeds could be eliminated through endosomal-lysosomal or Galectin-8-mediated (green hexagon) autophagic system. Once escaping from the damaged endosomal vesicles, tau seeds sequester cytoplasmic inert tau and template the formation of new seeds in a prion-like mechanism. (D) Tau seeds spread along synaptically connected neurons to affect large-scale brain networks, leading to the stereotypical propagation of tau pathology.

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Table of Contents Graphic

Manuscript title: Pathological Changes of Tau Related to Alzheimer’s Disease Authors: Dandan Chu and Fei Liu

For Table of Contents Use Only

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Figure 1 99x58mm (300 x 300 DPI)



Figure 2 141x152mm (300 x 300 DPI)


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Table of contents graphic 95x34mm (300 x 300 DPI)


Pathological Changes of Tau Related to Alzheimer's Disease - ACS

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