Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target

Abstract

Tau plays an important pathological role in a group of neurodegenerative diseases called tauopathies, including Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration. In each disease, tau self-assembles abnormally to form filaments that deposit in the brain. Tau is a natively unfolded protein that can adopt distinct structures in different pathological disorders. Cryo-electron microscopy has recently provided a series of structures for the core of the filaments purified from brain tissue from patients with different tauopathies and revealed that they share a common core region, while differing in their specific conformation. This structurally resolvable part of the core is contained within a proteolytically stable core region from the repeat domain initially isolated from AD tau filaments. Tau has recently become an important target for therapy. Recent work has suggested that the prevention of tau self-assembly may be effective in slowing the progression of Alzheimer's disease and other tauopathies. Here we review the work that explores the importance of tau filament structures and tau self-assembly mechanisms, as well as examining model systems that permit the exploration of the mode of action of potential inhibitors.

Amyloid Cross-Seeding: Mechanism, Implication, and Inhibition

“…The components of the PHF core are composed mainly of MTBR, which is truncated at E391 (C terminal), but the enzyme responsible remains unexplored [ 89 ]. Apart from AD, tau is also involved in other diseases such as Pick’s disease (straight filament (SF) aggregation), chronic traumatic encephalopathy (hyperphosphorylated tau with PHF and SF), and corticobasal degeneration (hyperphosphorylated tau) [ 90 ].…”

The Diagnostic Potential of Amyloidogenic Proteins

“…Tau is a major microtubule-associated protein that stabilizes the microtubules in neurons [ 2 , 40 ]. In human brains, tau exists as six different isoforms that carry either three or four microtubule-binding repeats (R).…”

“…As an example, in AD, ALS, FTD and Parkinsonism, both 3R and 4R amyloids are present, while in corticobasal degenerations and Pick’s disease only 4R and 3R amyloids, respectively, are found [ 41 , 42 ]. Tau undergoes PTMs, particularly phosphorylation [ 40 ]. Pathological hyperphosphorylation reduces tau affinity for microtubules and causes its detachment from microtubules, resulting in the formation of PHFs and NFTs [ 2 ].…”

“…Pathological hyperphosphorylation reduces tau affinity for microtubules and causes its detachment from microtubules, resulting in the formation of PHFs and NFTs [ 2 ]. To date, 85 potential phosphorylation sites of tau have been identified [ 40 ]. Furthermore, molecular and cellular studies revealed that acetylation (e.g., Lys174, Lys274 and Lys280), oxidation (e.g., Cys322), nitration (e.g., Tyr29), glycation (e.g., Lys87, Lys132 and Lys150), truncation (e.g., at Asp13 and Asp421 and Glu391) and ubiquitination (e.g., Lys48 and Lys63) also affect tau aggregation [ 27 ] ( Table 1 ).…”

Dityrosine cross-links are present in Alzheimer’s disease-derived tau oligomers and paired helical filaments (PHF) which promotes the stability of the PHF-core tau (297-391) in vitro

“…Under normal conditions, tau is soluble and intrinsically disordered. However, post-translational modifications, truncation in disease, mutations or cellular stress conditions influence its structure and propensity to aggregate (Martin et al, 2011, Oakley et al, 2020). Indeed, SFs and PHFs are formed from the pathological assembly of tau monomers to dimers, then oligomers and eventually fibrils, which deposit as NFTs.…”