Intraneuronal filamentous tau inclusions such as neurofibrillary tangles (N
FTs) are neuropathological hallmarks of Alzheimer's disease (AD) and relate
d sporadic and familial tauopathies, NFTs identical to those found in AD br
ains have also been detected in the hippocampus and entorhinal cortex of co
gnitively normal individuals as they age. To recapitulate age-induced NFT f
ormation in a mouse model, we examined 12- to 24-month-old transgenic (Tg)
mice overexpressing the smallest human brain tau isoform, These Tg mice dev
elop congophilic tau inclusions in several brain regions including the hipp
ocampus, amygdala, and entorhinal cortex. NFT-like inclusions were first de
tected in Tg mice at 18 to 20 months of age and they were detected by histo
chemical dyes that bind specifically to crossed beta -pleated sheet structu
res (eg, Congo red, Thioflavin S), Moreover, ultrastructurally these lesion
s contained straight tau filaments comprised of both mouse and human tau pr
oteins but not other cytoskeletal proteins leg, neurofilaments, microtubule
s). Isolated tau filaments were also recovered from detergent-insoluble tau
fractions and insoluble tau proteins accumulated in brain in an age-depend
ent manner. Thus, overexpression of the smallest human brain tau isoform re
sulted in late onset and age-dependent formation of congophilic tau inclusi
ons with properties similar to those in the tangles of human tauopathies, t
hereby implicating aging in the pathogenesis of fibrous tau inclusions.