Neurodegenerative Tauopathies

TLDR

Tauopathies, such as Alzheimer’s disease, corticobasal degeneration, progressive supranuclear palsy, Pick’s disease, and FTDP‑17, are marked by filamentous tau inclusions and amyloid β deposits, with tau gene mutations and polymorphisms driving disease etiology and phenotypic variability. Transgenic models are increasingly available to test and validate mechanisms of neurodegenerative tauopathies, accelerating discovery of more effective therapies for these disorders and related diseases such as Alzheimer’s disease.

Abstract

▪ Abstract The defining neuropathological characteristics of Alzheimer's disease are abundant filamentous tau lesions and deposits of fibrillar amyloid β peptides. Prominent filamentous tau inclusions and brain degeneration in the absence of β-amyloid deposits are also hallmarks of neurodegenerative tauopathies exemplified by sporadic corticobasal degeneration, progressive supranuclear palsy, and Pick's disease, as well as by hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Because multiple tau gene mutations are pathogenic for FTDP-17 and tau polymorphisms appear to be genetic risk factors for sporadic progressive supranuclear palsy and corticobasal degeneration, tau abnormalities are linked directly to the etiology and pathogenesis of neurodegenerative disease. Indeed, emerging data support the hypothesis that different tau gene mutations are pathogenic because they impair tau functions, promote tau fibrillization, or perturb tau gene splicing, thereby leading to formation of biochemically and structurally distinct aggregates of tau. Nonetheless, different members of the same kindred often exhibit diverse FTDP-17 syndromes, which suggests that additional genetic or epigenetic factors influence the phenotypic manifestations of neurodegenerative tauopathies. Although these and other hypothetical mechanisms of neurodegenerative tauopathies remain to be tested and validated, transgenic models are increasingly available for this purpose, and they will accelerate discovery of more effective therapies for neurodegenerative tauopathies and related disorders, including Alzheimer's disease.