Research Article: A walk through tau therapeutic strategies

Date Published: February 15, 2019

Publisher: BioMed Central

Author(s): Santosh Jadhav, Jesus Avila, Michael Schöll, Gabor G. Kovacs, Enikö Kövari, Rostislav Skrabana, Lewis D Evans, Eva Kontsekova, Barbara Malawska, Rohan de Silva, Luc Buee, Norbert Zilka.

http://doi.org/10.1186/s40478-019-0664-z

Abstract

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer’s disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer’s disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade.

Partial Text

Tau protein is considered to be one of the most peculiar proteins in the central nervous system. It is located in several cell compartments, including the axon, dendrites, nucleus, nucleolus, cell membrane and synapses [310]. However, tau is also present in the interstitial fluid [284, 370], and can pass into cerebrospinal fluid (CSF), where it is found at concentrations of 10-25 pg/ml (pT181-tau) or 300-400 pg/ml (tau) [28, 29, 248]. In physiological conditions, extracellular tau may enter neurons either via a dynamin-mediated endocytic mechanism or by classical endocytosis [95]. In neurodegenerative tauopathy, diseased modified tau can propagate along neuroanatomically connected brain areas via multiple mechanisms and spread tau pathology throughout the brain [231].

In contrast to amyloid precursor protein (APP), the function of tau protein was already known at the time of the discovery of it as a constituent of neurofibrillary degeneration. Tau is a microtubule-associated protein (MAP), promoting the polymerization and assembly of microtubules [351]. In the adult human brain, there are six isoforms of tau protein generated by alternative splicing from a single gene located on chromosome 17 [120, 238]. At the N-terminal end, they differ by the addition of a 29 amino-acid sequence (1 N) or as replicates (2 N – total of 58 amino acids) coded by exons 2 and 3. The sequence coded by exon 3 is only present if the sequence encoded by exon 2 is inserted. Interestingly, the 2 N tau isoforms are weakly expressed in the human brain [119, 214, 295]. The microtubule binding region (MTBR), has three (3R: R1, R3, R4) or four repeat domains (4R: R1-R4). The sequence encoded by exon 10 allows the insertion of a 31 amino acid microtubule binding domain (R2) which is inserted after the first repeat R1. Tau isoforms with 3R and 4R are equally expressed, since their ratio is about 1:1 in the human brain [295]. However, some neurons do not express 4R tau isoforms. For instance, granular cells of the dentate gyrus only express mRNAs of 3R-tau isoforms [119]. Thus, tau isoforms have different cellular and laminar distribution in the human brain [46].

AD is a double proteinopathy, characterized by the presence of both tau-reactive neurofibrillary lesions and β-amyloid (Aβ) depositions (senile plaques; SPs). The importance of both proteins, which are present also under physiological circumstances, in the development of AD is extensively debated. Numerous clinicopathological studies were published, favouring both histological lesions, i.e. NFTs and SPs. However, since the early nineties, most studies found a strong correlation between neocortical NFT load and cognitive impairment [94].

Recently, the development of positron emission tomography (PET) radioligands presumably binding to tau has enabled the in vivo mapping and quantification of tau pathology, hitherto largely confirming autopsy findings. The radioligand [18F] Flortaucipir (FTP, previously AV1451 or T807), a benzimidazole pyrimidine derivative, is by far the most widely employed to date. It has been shown to bind with high affinity to mixed 3R- and 4R-tau isoforms in paired-helical filaments (PHF) of AD patients [26, 309, 361]. A recent study furthermore showed that in vivo FTP-binding and post mortem PHF load were highly correlated in a subject with a MAPT R406W mutation, which causes AD-like 3R/4R tau pathology [309]. However, large inter- and intra-individual differences were observed in a recent autopsy study of several tauopathies [361], calling for further investigation of FTP binding characteristics.

In pathological conditions, tau protein undergoes post-translational modifications, such as, truncation [241, 242, 357, 358], phosphorylation [127], ubiquitination [32, 181], glycation [283, 373], glycosylation [196, 343], nitration [144, 271, 272] and sumoylation [87, 209]. Among them, phosphorylation and truncation are the most studied. Many laboratories suggest that tau hyperphosphorylation on Ser and Thr residues facilitates tau aggregation. Tau is posttranslationally modified at Ser/Thr residies by O-linked N-acetylglucosamine (O-GlcNAc), and thus increasing tau O-GlcNAcylation may protect against tau aggregation. In tau transgenic mouse models, inhibition of β-N-acetyl-glucosaminidase, the enzyme responsible for O-GlcNAc removal, is protective [33].

In Alzheimer’s disease, tau protein is burdened by numerous post-translational modifications resulting in aggregation and tangle formation. Therefore, a number of passive vaccines for tau immunotherapy raised against various epitopes or conformation/s of tau have been developed, showing varied degrees of efficacy in attenuating tau pathology in animals, along with improvement in cognitive or motor functions. Several animal models have been used for testing of the therapeutic efficacy of monoclonal antibodies. Tau pathology is localized in various brain areas including hippocampus and brainstem. The location of tau pathology is mostly determined by the gene promotor. The clinical presentation is driven by topographic distribution of tau pathology, some of rodent models demonstrated cognitive decline while others suffer from impairment of sensori-motor functions [383]. The majority of preclinical studies have been performed on transgenic mice expressing mutant tau proteins (Table 1). However, tau mutations are not linked to familial forms of AD, but can cause frontotemporal dementia.Table 1Tau antibodies tested in preclinical efficacy studiesANTIBODYEPITOPEANIMAL MODELIMPROVEMENTEFFICACYREFERENCECognitiveMotorNFTsInsoluble tauPHF1pS396/404P301Lnd.nd.nd.Reduced[56]P301Snd.ImprovedReducedReducedMC1aa7–9 and aa 313–322P301Lnd.nd.nd.ReducedP301Snd.ImprovedReducedReducedMC1aa7–9 and aa 313–322P301Lnd.nd.ReducedNo change[72]DA31aa150–190No changeNo changePHF1pSer396/404ReducedReduced4E6G7379-408 (pS396/404)P301Lnd.nd.ReducedNo change[129]6B2G12TOMAnd.Tg2576ImprovedImprovednd.Reduced[54]PHF6pT231rTg4510ImprovedNo changend.No change[281]PHF13pS396rTg4510ImprovedNo changend.No changePS19Improvednd.ReducedNo changeHJ9.3aa306–320P301SImprovedNo changeReducedReduced[375]HJ9.4aa7–13Moderate changeNo changeReducedNo changeHJ8.5aa25–30Moderate changeNo changeReducedReducedHJ8.5aa25–30P301Snd.ImprovedReducedReduced[374]43Daa6–183xTg-ADImprovednd.Reducednd.[73]77E9aa184–195Improvednd.Reducednd.AT8pS202 + pT2053xTg-ADnd.nd.Reducednd.[342]MAb86pS422TauPS2APPnd.nd.Reducednd.[61]pS404 mAb IgG2pS404K3 and pR5nd.nd.ReducedReduced[151]pS409-taupS409P301Lnd.nd.ReducedReduced[182]Armanezumabaa2–18THY-Tau22nd.nd.Reducednd.[4]PHF1pS396/404P301Lnd.ImprovedReducedNo change[36]Ta9pS396tau609Improvednd.ReducedReduced[328]tau784Ta4pSer396tau609ImprovedNo changeReducedReducedtau784Ta1505pSer413tau609Improvednd.ReducedReducedDC8E8aa268-273, aa299-304, aa330-335, aa362-367R3/m4nd.nd.ReducedReduced[168]nd Not defined

Like their passive immunotherapy counterparts, active vaccines targeting the mid-region, microtubule binding domain and C-terminus have been extensively investigated in preclinical studies (Table 2). Most of these studies demonstrated reduction in tau pathology [14, 30, 167, 270, 274, 322] along with improvement in cognitive or sensorimotor abilities in animals [36, 37, 167, 322, 326] (Table 3).Table 3Preclinical studies on tau vaccinesIMMUNOGENANIMAL MODELIMPROVEMENTEFFICACYREFERENCECognitiveSensorimotorNFT’sInsoluble tauTau379–408 [pS396,404]P301LNo changeImprovedDecreasedDecreased[14]Tau 379-408 [pS396/404]htau/PS1M146LImprovedImprovedReducedReduced[36]Tau 417-426 [pS422]Thy-Tau22Improvednd.ReducedReduced[326]Tau393-408 [pS396/S404] (Liposome based)P301Lnd.ImprovedNo changeReduced[322]Tau379-408 [pS396/S404]hTau X PS1ImprovedNo changeReducedReduced[37]hTauImprovedNo changeNo changeReducedhTau/PS1/mTauImprovedNo changeNo changeReducedTau195-213 [pS202/T205]DM-Tau-tgnd.nd.Reducednd.[30]Tau207-220 [pT212/S214]nd.nd.Reducednd.Tau 224-238 [pT231]nd.nd.Reducednd.Tau aa395-406 [pS396/404]pR5nd.nd.Reducednd.[25]Human paired helical filaments (PHF’s)THY-Tau22nd.nd.ReducedReduced[12]Tau229-237 [pT231/pS235]P301Snd.nd.nd.nd.[273]Tg2576Tau199–208 [pS202/pT205]P301Snd.ImprovedNo changeNo change[274]nd.ImprovedNo changeNo changeTau209–217nd.ImprovedNo changeNo changeTau 294-305SHR72 ratsnd.ImprovedReducedReduced[167]Tau 379-408 [pS396/404]3xTg-ADNo changend.ReducedReduced[270]Tau 294-305P301SImprovedReducedReduced[157]nd Not defined

Direct targeting of tau gene (MAPT) expression is gaining currency as a therapeutic approach with an antisense oligonucleotide (ASO) therapy already in Phase I clinical trials. Several in vivo and cell studies have demonstrated the benefit of tau reduction in slowing pathological progression and improving functional deficits in tauopathy models both dependent and independent of ß-amyloid pathology. Tau reduction also results in significant improvements in seizures associated with AD pathology and in a model for Dravet syndrome [112].

Surplus availability of unbound tau, particularly of the more fibrillogenic mutants or 4R-tau could, with abnormal hyperphosphorylation, lead to mislocalisation and aberrant interaction with other cellular components and milieux. This leads to conformational conversion of tau from its highly soluble, intrinsically disordered characteristic to the seed-competent aggregation-prone form [228]. This has led to the notion that reduction of total tau (or surplus 4R-tau) could be therapeutically beneficial. Although the recent stable of passive immunotherapy approaches targeting tau could be blockading intercellular transmission of pathological tau seeds, a plausible mechanism could also be a reduction of pathological tau mediated by microglial or neuronal uptake and clearance of extracellular tau-antibody complexes [107, 210, 223].

This is an exciting juncture in the hunt for therapies against neurodegenerative disorders by directly targeting those causative genes. The efficacy and safety of ASO therapy has been demonstrated in clinical trials for nusinersen (Spinraza®; ClinicalTrials.gov Identifier: NCT02193074) for the treatment of spinal muscular atrophy (SMA) and eteplirsen (Exondys51®; NCT00844597, NCT01396239/NCT01540409, NCT02255552) to treat Duchenne muscular dystrophy (DMD). More recently, IONIS-HTTRx (RG6042; NCT02519036) was tested for the treatment of Huntington’s disease (HD) [317]. This specifically targets the mutant, expanded huntingtin gene (HTT) mRNA and supresses its expression. A recent Phase 1/2a clinical trial with intrathecal delivery of the ASO has had no adverse drug-related incidents and showed promising reduction of mutant HTT mRNA levels in CSF [317].

Hyperphosphorylated and truncated tau protein is susceptible to aggregation and loss of cytoskeletal microtubule-stabilizing properties, leading to neuronal damage and cell death. Compounds able to prevent aggregation may represent a promising strategy for effective treatment of Alzheimer’s disease [162, 356]. Two major approaches focus on phosphorylation of tau and prevention of tau oligomerization. The former involves the search for inhibitors of kinases which phosphorylate tau or phosphatase activators which dephosphorylate the protein [5, 189]. The latter seeks direct inhibitors of the tau aggregation process.

Tau is a multifaceted protein with a plethora of physiological functions. In the disease condition, tau protein drives neurodegeneration and causes neurodegenerative disorders such as Alzheimer’s disease. Pathologically modified tau has become an important therapeutic target for AD and related tauopathies. Although no disease-modifying treatments are yet available, many new therapeutic approaches targeting pathological forms of tau are being tested in clinical trials. Disease-modifying therapy is aimed at preventing, slowing or ameliorating the production, oligomerisation, aggregation and deposition of pathological tau protein. The most promising therapeutic strategies include active tau vaccines and therapeutic monoclonal antibodies. Besides immunotherapy, there are many other therapies currently being explored in the treatment of tau neurodegeneration such as modulation of tau phosphorylation, inhibition of tau aggregation or regulation of its expression. While waiting for the results of ongoing clinical trials, we can continue to unravel the complexities of tau proteome and different biological functions of this peculiar brain protein.

 

Source:

http://doi.org/10.1186/s40478-019-0664-z