Tau and neurodegeneration

Abstract

First identified in 1975, tau was implicated in Alzheimer's disease 10 years later. Filamentous tangle inclusions were known to be made of hyperphosphorylated tau by 1991, with similar inclusions gaining recognition for being associated with other neurodegenerative diseases. In 1998, mutations in MAPT, the gene that encodes tau, were identified as the cause of a dominantly inherited form of frontotemporal dementia with abundant filamentous tau inclusions. While this result indicated that assembly of tau into aberrant filaments is sufficient to drive neurodegeneration and dementia, most cases of tauopathy are sporadic. More recent work in experimental systems showed that filamentous assemblies of tau may first form in one brain area, and then spread to others in a prion-like fashion. Beginning in 2017, work on human brains using high-resolution techniques has led to a structure-based classification of tauopathies, which has opened the door to a better understanding of the significance of tau filament formation.

Keywords: tau filaments; tau gene mutations; tau isoforms; tauopathies.

Figure 1

Human brain tau isoforms. MAPT and the six tau isoforms expressed in adult human brains. MAPT consists of 14 exons (E). Alternative mRNA splicing of E2 (red), E3 (green) and E10 (yellow) gives rise to six tau isoforms (352–441 amino acids). The constitutively spliced exons (E1, E4, E5, E7, E9, E11, E12, and E13) are shown in blue. E6 and E8 (violet) are not transcribed in human brains. E4a (orange) is only expressed in the peripheral nervous system. The repeats (R1-R4) are shown, with three isoforms having four repeats (4R) and the other three isoforms having three repeats (3R).

Figure 2

Mutations in MAPT in FTDP-17 T. Gene dosage mutations, where one allele of MAPT is doubled, as well as missense, deletion and intronic mutations in MAPT are dominantly inherited. (Fifty-five coding region and eleven intronic mutations are shown.) They give rise to 65 different forms of FTDP-17 T (pathogenic intronic mutation –15/+4 is compound heterozygous).

Figure 3

Structure-based classification of tauopathies. The dendrogram shows the proposed classification, with the corresponding folds displayed with the first β-strand in R3 oriented approximately horizontally, except for the globular glial tauopathy (GGT) and globular glial tauopathy-progressive supranuclear palsy-tau (GPT) folds, which are aligned to the progressive supranuclear palsy (PSP) fold. Internal, nonproteinaceous densities are shown in black. AD, Alzheimer’s disease; AGD, argyrophilic grain disease; ALS/PDC, amyotrophic lateral sclerosis/parkinsonism–dementia complex; ARTAG, age-related tau astrogliopathy; CBD, corticobasal degeneration; CTE, chronic traumatic encephalopathy; FBD, familial British dementia; FDD, familial Danish dementia; GSS, Gerstmann-Sträussler-Scheinker disease; LNT, limbic-predominant neuronal inclusion body 4R tauopathy; PART, primary age-related tauopathy; PiD, Pick’s disease; SSPE, subacute sclerosing panencephalitis.