Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation

Abstract

Tau protein plays a major role in the pathogenesis of Alzheimer’s disease. Despite many decades of intensive research, the cause of the conformational switch that leads to the remodeling of the highly flexible conformational ensemble of intrinsically disordered protein tau into insoluble filaments is still elusive. We show here that truncation of tau may play a causative role in this conformational change, as evidenced by results obtained from in vitro experiments and from transgenic animal models. This conformational change is a common denominator of pathological tau protein assemblies, and a salient drug target. The long-running research of truncated tau has led to the generation of the first active tau vaccine that has entered clinical trials.

Keywords

Aggregation Alzheimer’s disease conformational ensemble immunotherapy tau protein truncation

Introduction

Ever since cognitive loss and dementia at an advanced age were understood to be due to a pathophysiological process, and not a natural part of aging, therapeutic efforts for neurodegenerative disorders have been both intense and diverse (see [1] for a recent review).

Tau

The key role of tau protein in Alzheimer’s disease (AD) was obvious and plain to see; no AD patient has developed dementia without extensive neurofibrillary pathology, and vice versa, patients at a Braak stage of 5 or 6 are rarely, if ever, cognitively intact [2] (for the rare occurrences of high Braak stages being assigned to cognitively normal individuals, one has to ask the question whether the score was assigned based on an isolated tangle in a brain region that usually develops pathology at later stages). Neurofibrillary pathology was found to correlate with the severity of dementia, and its distribution with the phenotype of cognitive impairment and affected domains of cognition [3 –5]. The case for tau as a driver of neurodegeneration is even clearer in the various tauopathies, where pure tau pathology, often tied to a MAPT mutation, leads to neurodegeneration [6, 7]. Recent research has also revealed the most likely mode of propagation of neurofibrillary lesions, a prion-like spreading via “tauons”, intercellularly transmissible tau moieties that serve as templates for tau aggregation [8], resulting ultimately in the deposition of tau in filaments with high beta sheet content [9]. While these tauons constitute natural drug targets, how they come into being is anybody’s guess though, and the scientific community is far from unified in regard to their key features and common denominators.

Then, what is there to a tauon, what key features? What can be used to tell it apart? First of all, it is important to highlight that, opposed to the 6 isoforms seen in health, the diseased tau proteome is extremely diverse, even at the level of protein sequence: as a result of truncation, fragments of various length arise [10]. Fragments containing the N-terminus but without the microtubule-binding repeats (MTBR) seem to preferentially find their way into the cerebrospinal fluid (CSF) [11], whereas all aggregating tau species participating in the formation of neurofibrillary pathology have at least a portion of the MTBR intact [9, 12]. Aggregation is an essential part of prion-like template-mediated conformational change, thus all tauons contain the MTBR or a part thereof. Truncation was shown to greatly promote the aggregation of tau [13], but the neo-epitopes created by truncation may not be the best immunotherapy targets, as even pathological tau molecules can become even further truncated, losing these epitopes in the process [14] (Fig. 1).

A further layer of diversity is provided by various other post-translational modifications of tau— ubiquitination, nitration, glycation, O-GlcNAcylation, or phosphorylation. Using phosphorylation as an example, the variability of tau becomes apparent once we consider that of the protein’s 441 amino acids (in the 2N4R isoform), roughly 80 are serine, tyrosine, or threonine that can be phosphorylated. The phosphorylation is subject to a vigorous flux, with kinases attaching phosphates, and phosphatases (e.g., PP2A) wiping the phosphates away again. It is clear that tau is excessively phosphorylated in AD [15], and it is likely that disturbance of the phosphorylation-dephosphorylation cycle can cause tauopathy, e.g., the Parkinsonism-Dementia complex of Guam [16]. The most relevant question, though, is whether any given phospho-epitope is present in all tauons, or at least a significant portion thereof.

Fig.1

Impact of truncation on the conformation of tau. Equilibrium between the healthy form of full-length tau (A) and a misdisordered form [56] of healthy tau (B) is shifted toward the healthy form, whereas for truncated tau (C, D) the opposite holds true: the misdisordered form (D) is the energetically preferred state. The conformational ensemble of truncated tau has a far greater accessibility of its MTBR and this increases its propensity for homooligomerization (E), hyperphosphorylation (F), and aggregation even with healthy tau (G).

To summarize: 1) all tauons will inevitably contain the MTBR, 2) they may or may not possess one or both intact termini, though truncation is widely prevalent, 3) they are likely to possess excessive phosphorylation and other post-translational additions, but the pattern is likely not uniform, and 4) they consist likely of multiple aggregated tau molecules (some studies report the smallest stable unit to be an 3-mer [17], though tau monomers possess pro-aggregant traits, and were shown to be able to attain and maintain pathological conformations following truncation).

Tau-targeted therapies have taken both the small-molecule and immunotherapy approach.

Small-molecule approaches were focused on inhibiting tau aggregation, e.g., methylthioninum [18], taxanes and other microtubule stabilizers to counteract cytoskeletal destabilization caused by pathological tau [19, 20], kinase inhibitors to reduce tau phosphorylation [21], or neurotrophic peptides with anti-phosphorylation properties (davunetide) [22]. None of these approaches were successful as of today.

The first tau-targeted immunotherapy, AADvac1, has entered clinical development in 2013 [23]; the compound stimulates the production of antibodies against a phosphorylation-independent conformational epitope found in the MTBR of tau. These antibodies are expected to prevent tau aggregation, intercept tauons, and opsonize them, so that they are taken up by microglia and removed (see Fig. 3).

Multiple tau-targeted immunotherapies have since then entered clinical development:

ACI-35, an active immunotherapy raising antibodies against the pS396/pS404 epitope, hypothesized to target extracellular spreading tau [24];

BIIB092, a humanized IgG4 monoclonal antibody targeted against extracellular N-terminal tau fragments [25];

C2N 8E12, a humanized monoclonal antibody targeted against extracellular tau [26];

RG7345, a humanized monoclonal antibody targeting the tau phospho-epitope pS422. Unlike the other immunotherapies discussed here, the antibody primarily aims to target intracellular tau [27]. The development of RG7345 was discontinued for undisclosed reasons.

Fig.2

Experimental characterization of truncated tau151-391/4R. A) Heparin induced oligomerization reaction of truncated and full length tau monitored by ThS fluorescence, O/N-overnight. B) AFM image of the product of 48 hours long heparin induced tau oligomerization reaction of tau151-391/4R. C) Phosphorylation reaction of AT100 epitope [74]. D, E) Microtubule assembly assay monitored by increase in OD at 340 nm and EM images of microtubules induced by full length and truncated tau (adapted from [70]). F) K_A values and SPR sensorgrams for the interaction of DC8E8 antibody with full length and truncated tau (adapted from [54]).

Fig.3

Proposed mechanism of action of AADvac1. AADvac1 leads to the production of antibodies that prevent tau aggregation, immobilize tauons, and flag them for removal by the immune system.

The indications for which these compounds are being developed follow clear trends:

AD as the most common tauopathy.

PSP as a pure tauopathy with high phenotype-pathology correlation, a good diagnostic accuracy, and swifter progression than AD (allowing shorter time frames for clinical efficacy readouts) [28].

Few tau-targeted compounds, with the notable exception of LMTM [18], were tested in the behavioral variant frontotemporal dementia; the indication has the major drawback that tau pathology underlies only ∼50% of bvFTD cases, and the other 50% display mostly TDP43 pathology, but neither the phenotype nor imaging or CSF biomarkers are sufficiently informative about which pathology is present in a given case [29].

nfvPPA, a phenotype of primary progressive aphasia mostly associated with tau pathology is a recent target of tau-targeted therapy (NCT03174886); the indication’s main appeal is the fact that the progression of language-dominated symptoms (and thus the impact of therapies) is assessable even while patients are non-demented; also, the phenotype is initially free of motor symptoms that would limit survival, again facilitating trial conduct [29, 30].

MAPT mutation carriers constitute a natural population for the testing of tau-targeted therapies, but their numbers are severely limited; also, tau mutations are very variable in their age of onset and symptom presentation [31].

Corticobasal syndrome as a 4-repeat tauopathy is also a potentially suitable indication for the development of tau-targeted therapies; the link between the CBS clinical phenotype and the corticobasal syndrome pathology is weaker than in the case of PSP, though [29]. In some studies, patients with either indication are enrolled to increase recruitment (e.g., NCT02133846).

Amyloid-β

Due to the fact that a small fraction of AD cases are caused by monogenic mutations in amyloid-β protein precursor (AβPP) or the presenilin 1 and 2 enzymes involved in its processing, the amyloid hypothesis of AD has received massive attention. Similarly, the fact the APP gene is located on chromosome 21, which is present in triplicate in Down syndrome patients who suffer from progressive neurodegeneration, has lent further support to the hypothesis [32]. Therapeutic approaches targeting basically all aspects of the proposed amyloid cascade have been tested, e.g.:

Immunotherapy aimed at removing the amyloid-β (Aβ) peptide:

active vaccines, e.g., AN1792 [33] and CAD106 [34];

passive vaccines, e.g., bapineuzumab [35], solanezumab [36], gantenerumab [37], aducanumab [38].

Amyloid aggregation inhibitors [1].

Molecules affecting the enzymes involved in AβPP processing (secretases), aiming to reduce production of Aβ [1]

Despite intense efforts, no anti-amyloid treatment was proven to be efficacious yet, even in cases where extensive clearance of amyloid deposits was achieved [35]. Furthermore, intervening in amyloid processing was found to be a non-trivial matter, as the various enzymes involved possess other vital functions, and interfering with them results in very poor safety profiles [39, 40].

The current consensus amongst proponents of the amyloid hypothesis appears to be that Aβ just initiates the AD pathophysiological process, and if an anti-amyloid strategy is to be effective, intervention is necessary prior to widespread generalization of neuropathology. As a result, anti-Aβ therapies are shifting their attention to ever-earlier stages of AD (e.g., DIAN, A4, API). Important questions, such as why massive amyloidosis without tau pathology is asymptomatic, still remain unanswered [4].

Other approaches

Covering every single facet of AD therapy development is beyond the scope of this article. Suffice to say, as diverse as the hypotheses about pathophysiology of AD are, so diverse are the treatment approaches. Neuroinflammation is a salient feature of AD [41] and numerous anti-inflammatory approaches have been tried in the clinic (anti-inflammatory drugs, statins, etc.). As aging is the primary risk factor for AD, numerous studies were conducted on nutrition supplements, hormones, and trophic factors in an attempt to slow or reverse brain aging [1]. Finally, non-pharmacological approaches, comprising optimization of dietary, blood pressure medication, and diabetes therapy, and intense physical and cognitive exercise were found to reduce dementia incidence in an at-risk elderly population [42], indicating that they will be a valuable companion therapy to disease-modifying agents once these are developed.

Evidence for Pathophysiological Tau Truncation in Vivo

Truncated tau proteins were initially identified as constituents of the pronase-resistant paired helical filament (PHF) core [43, 44]. The first evidence of tau truncation in the AD brain was obtained via the monoclonal antibody MN423, which recognizes tau proteins truncated at Glu391 [12]. Later, it was found that tau protein is cleaved by caspases at several sites, especially at Asp421 by caspase-3 [45, 46]. The disease specificity of certain truncation/conformation patterns becomes apparent when analyzing the brain via antibodies such as the truncation-dependent conformational antibody DC11, which recognizes solely conformationally modified tau proteins from AD brains and does not recognize tau proteins from healthy brains. Its AD-specific conformational epitope can be reconstituted in vitro by truncation of recombinant tau, indicating that disease-specific tau conformations arise naturally when tau is truncated [47, 48].

Zilka et al. have performed tandem-affinity purification of the sarcosyl-insoluble protein fraction from the human AD brain (Braak V) using antibodies specific for extreme N-and C-termini of tau and have shown the presence of both N- and C-terminally truncated forms of tau protein, including the previously identified tau fragment that constitutes the core of PHF. The presence of this fragment (dGAE) was verified with MS analysis and proves its presence in pronase-untreated PHFs, resolving the long-running debate whether tau truncation is an artifact of pronase treatment, or arises naturally in disease [10].

Derisbourg et al. have identified several new N-terminal truncation sites using LC-MS/MS analysis of brain extracts from controls and AD patients after immunoprecipitation with the Tau5 antibody (epitope 218–225). They have chosen truncation sites Met11 and Gln124 for further biochemical analysis. The tau fragment starting at Gln124 showed a stronger ability to bind microtubules and protect them from depolymerization compared to full length tau 1N4R. This effect can lead to impaired synaptic plasticity, and to wasteful and inefficient microtubule assembly. The phosphorylation status was evaluated after transfection of corresponding expression vectors into N1E-115 neuroblastoma cell line and subsequent western blot analysis after 48 hours. The construct starting at Met11 displayed an increase in phosphorylation at the Thr231 epitope, and no difference in phosphorylation at Ser396 compared to full length tau 1N4R. Interestingly, the construct starting at Gln124 displayed a decrease in phosphorylation at Thr231 and Ser262/356 compared to full length tau 1N4R, indicating that truncated tau molecules possess different propensities toward (hyper)phosphorylation [49].

Effect of Truncation On The Structural Properties of Disordered Tau Molecule: Pathologic Toxic Gain of Function

Tau is a typical intrinsically disordered protein (IDP) [50, 51]. The structure of an IDP cannot be described by a single conformation, but rather by a set of different conformational states, commonly designated a ‘conformational ensemble’ (CE). Each member of the IDP CE occupies one of the local energy minima on the energetic landscape, with low barriers between them [52]. Similarly, an individual conformational state can be seen as a sub-set of the CE, whose members are freely interconverting conformers. Taken together, the CE of an IDP is defined by its individual members and by the distribution of IDP molecules between them [50]. It has to be underlined that the biological activity of IDPs is completely determined by the composition of their CE, which is encoded by IDP sequence, posttranslational modifications, environment, binding partners, etc.

It was observed that IDPs can support several non-standard modes of allosteric regulation, consisting generally of a conformational remodeling of their CE after a signal-inducing event, such as posttranslational modification (e.g., phosphorylation), binding of a small ligand or other molecule, etc. [53]. This conformational remodeling consists of a repopulation of individual conformational states and changing the distribution of IDP molecules between them. For example, augmenting a state that features an exposed signal-transduction domain may kinetically boost IDP binding to receptors that have an affinity for said domain, and change the protein’s interactome considerably.

Intriguingly, truncation of tau emerges as an up to now overlooked inducer of tau CE remodeling. We have observed that truncation of both the 3R and 4R tau isoform results in an order of magnitude faster binding to conformational monoclonal antibody DC8E8 [54]. Faster binding reflects a greater accessibility of the DC8E8 epitopes that are located in the microtubule-binding repeat domain and indicates a change in the population of the CE of truncated tau in comparison to the CE of the full-length isoforms. As the DC8E8 epitope lies in the vicinity of the aggregation-prone tau domain, its exposure means that truncated tau has a lower entropic barrier to self-association, i.e., greater accessibility of the β-sheet forming domains, which inevitably fosters tau-tau interaction. These results are in agreement with the over-representation of truncated tau form in neurofibrillary pathology, and with the higher aggregation tendency of truncated tau (see below). Furthermore, we have observed in both primary rat neurons and human neuroblastoma cells that truncated tau lacking 150 N-terminal residues has constitutive access to the nucleus (unlike its full-length counterpart whose access is situational), where it engages in interactions with subnuclear structures [55]. Translocation into the nucleus is likely driven by the remodeled CE of truncated tau. We term the remodeled tau ensemble that’s in the process of transitioning from a soluble disordered protein to its insoluble, misordered aggregated form the “misdisordered” state of tau [56].

Truncated tau has been suggested to trigger neurofibrillary degeneration [12] and to drive the pathological conversion of wild-type tau at neuritic plaques [57]. In vitro tau aggregation studies with inducers of tau polymerization have shown that both C-terminal truncations of tau at Glu391 and at Asp421 lead to proteins more prone to aggregation than full length tau [58 –60]. Also, truncated tau151-391/4R aggregates more rapidly than full length tau upon addition of a polyanionic inducer (B. Kovacech, unpublished results, Fig. 2A). Some truncated tau variants aggregate readily and form PHF-like fibrils also without the addition of an inducer. This was shown for the PHF core tau fragment dGAE (tau297-391/4R) [61]. At low concentrations of dGAE, an inhibitory effect of disulfide bridge crosslinked dimers was observed, which was overcome at concentrations higher than 100μM [61]. The aggregation without an inducer was also observed for the mutated tau fragment K18Δ280 (tau243-372/4RΔ280) and tau fragment K12 (243-394/3R) [62].

Higher propensity of truncated tau for aggregation may lead to increased oligomer formation and cell to cell spreading, as tau oligomers were detected in mouse models expressing truncated tau protein. Experimental evidence clearly shows that tau truncation is a key step in the induction of tau pathology [63, 64]. According to the prion-like model of tau propagation, tau aggregates formed in a cell are released into the extracellular space, from which they are taken up into other cells, probably via the interaction with cell surface heparan sulfate proteoglycans that stimulate macropinocytosis [65]. The propagation may also occur trans-synaptically and/or via exosomes [66]. In the extracellular space, tau can be a target of matrix-metalloproteinases. In vitro it was shown that cleavage of tau by matrix-metalloproteinase 9 enhances formation of tau oligomers and tau fragments 204–330 or 262–391 containing parts of the tau microtubule-binding repeat region [67]. Moreover, a highly-complex polyanionic extracellular matrix may catalyze nucleation of tau oligomers [68]. The presence of tau oligomers in the interstitial space was shown by in vivo micro-dialysis from the rTg4510 mouse brain with a large-pore probe [69]. These findings lend themselves to the conclusion that the interstitial space can promote both tau truncation and oligomerization.

DC11 positive N- and C-terminally truncated tau proteins (except for tau99-441) exert 3-4 times higher microtubule assembly activity than full length tau and produce malformed, abnormally thick microtubule bundles [70]. Microtubule bundles were observed also in the presynaptic terminals of transgenic animals expressing tau151-391/4R; in this model, truncated tau was shown to deregulate synaptic markers in presynaptic compartments [71].

Expression of truncated tau151-391/4R in SH-SY5Y neuroblastoma cells induces caspase-3 independent apoptosis-like programmed cell death. The expression of truncated tau was significantly more toxic for the cells than the expression of full length tau [72]. It was also shown that expression of truncated tau in this cellular model suppresses the activity of the proteasome, thus inhibiting its own degradation [73].

The monitoring of simultaneous in vitro phosphorylation reactions of full length tau and truncated tau151-391/4R with a brain extract has shown that truncated tau is phosphorylated more rapidly and to higher extent than full length tau on several AD relevant phospho-epitopes (AT270, pS199, pT212, pS214, pS262, pS356, AT8, AT100). Particularly the AT100 epitope appears on truncated tau after 8 hours of reaction and the increase of its intensity on western blot is exponential, whereas on full length tau it is formed after 14 hours, with slow increase (Fig. 2C). This shows that truncation of tau leads to the change of conformation that is more accessible for kinases [74].

Phenotype of Transgenic Models Expressing Truncated Tau Protein

Modelling neurofibrillary pathology in transgenic models with full-length tau is hardly achievable without introducing a point mutation [75]. On the contrary, models with truncated tau protein as transgene easily reproduce pathological aspects of human tauopathies (for review, see [64]). The first rat model that established tau truncation as a factor sufficient to drive neurofibrillary degeneration in the absence of a tau mutation, transgenic line SHR318, was created by expressing tau 151-391/4R under the control of the mThy1 promoter [70]. More than 15 transgenic models created since then confirmed that animal models based on truncated tau reproduce pathological aspects of human tauopathies much more easily than those using full-length tau.

Truncated tau in transgenic models induces a type of pathology highly similar to AD, starting with the formation of progressively phosphorylated tau oligomers at a pre-tangle stage, and ending with insoluble tangles; these tangles are thioflavin-S reactive, Congo-red birefringent, and argyrophilic, thus displaying all signs of tangle maturity. Perhaps most importantly, truncated tau transgenes are able to sequester full-length endogenous rat tau into high-molecular weight aggregates, unlike other commonly used models where the pathology is composed solely of the transgenic tau [63 , 76–81].

Neurotoxicity of truncated tau is reflected in various neurobehavioral phenotypes, like motor impairment [77 , 81–87] and deficiency in short-term memory and spatial learning tasks [63 , 85–87].

Truncated tau transgenic models have been used for investigation of the changes in CSF due to neurofibrillary degeneration, leading to the proposal of various tauopathy CSF markers, namely metabolites [88], peptides [89], amino acids, [90, 91], and neurotransmitters [92]. Response to stress and the interplay between stress, neuroinflammation, and neurodegeneration has been extensively studied on truncated tau models as well [93 –95].

Therapeutic Approaches Targeting The Misfolding of Tau

A number of active vaccines targeting tau protein has been proposed. The first to be used in humans is the active vaccination with the N-terminally cysteinylated tau peptide ²⁹⁴KDNIKHVPGGGS³⁰⁵ coupled to KLH, designated ‘AADvac1’. It is designed to induce the production of antibodies against a newly identified domain that regulates tau oligomerization [96]. Safety, tolerability, and efficacy of AADvac1 are being evaluated in ongoing clinical trials [23]; NCT02579252; NCT03174886.

The component of AADvac1 that is designed to induce an antibody response against pathological tau protein, i.e., the peptide tau_{294 - 305} is derived from the epitope of the monoclonal antibody DC8E8 [54]. DC8E8 differs markedly from other tau-targeted immunotherapies in development in several aspects, including its ability to 1) inhibit tau-tau interaction, 2) bind tau at four different epitopes in the microtubule-binding repeat domain (MTBR), and 3) selectively recognize conformationally aberrant (misfolded) species of tau that are likely the driving force behind template-mediated tau aggregation and disease progression in AD and non-AD tauopathies [54, 97] (Fig. 3). The four homologous sequences in the MTBR of tau targeted by DC8E8 and by AADvac1-elicited antibodies (further referred to as “DC8E8 tetratope”) with the common amino acid pattern HxPGGG [54] are strategically placed throughout the domain of tau that’s essential for its assembly into filaments. The first and the second epitopes of the DC8E8 tetratope strategically precede the polymerization-prone, β-structure forming motifs ²⁷⁵VQIINK²⁸⁰ and ³⁰⁶VQIVYK³¹¹, respectively, which are considered the sites at which tau oligomerization is initiated [12 , 99].

In tau transgenic mice and rats, administration of DC8E8 and its active vaccine counterpart AADvac1 respectively led to a reduction in tau pathology, with decreased number of neurofibrillary tangles and depletion of the sarcosyl-resistant tau aggregates; a salient point is that while the targeted epitope is phosphorylation-independent, AADvac1 and DC8E8 treatment led to a pronounced reduction in hyperphosphorylated tau as well, highlighting that conformationally altered tau protein is most likely to become hyperphosphorylated [54, 96]. Considering its efficacy and binding properties, DC8E8 is a suitable candidate for clinical development, defining a new class of disease-modifying passive immunotherapeutics of AD.

Initial clinical results of AADvac1 are encouraging as well. The safety profile was very benign, indicating that tau pathology can be safely targeted in humans. No meningoencephalitis was observed; neither did AADvac1 treatment cause microbleeds or edema (ARIA-E, ARIA-H) that prove dose-limiting for many anti-amyloid therapies.

The vaccine was able to elicit an IgG antibody response against the tau peptide component in 29 of 30 elderly patients; in at least 25 of those patients, the antibody response was shown to target also truncated pathological tau protein 151-391/4R [23]. Perhaps most importantly, the induced immune response recognized tau protein extracts from AD brains in a titer-dependent manner, and the response from individual patients could detect pathological tau in all tested brain extracts, again highlighting the fact that the conformational epitope targeted by AADvac1 is a conditio sine qua non of tau aggregation.

Phase II results from tau-targeted immunotherapies are expected to become available in the near future (2019 and onwards).

Footnotes

Acknowledgments

This work was supported by the VEGA grant No. 2/0177/15 and by EU structural funds ITMS 26240220008, and by Axon Neuroscience SE.

Authors’ disclosures available online (.

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