The defining neuropathological characteristics of
Alzheimer's disease are abundant filamentous tau lesions and deposits of fibrillar
amyloid beta peptides. Prominent filamentous tau inclusions and brain degeneration in the absence of
beta-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.