application): Neurodegenerative disorders with prominent brain aggregates of tau filaments in neurons, and sometimes also in glia, are known as """"""""tauopathies"""""""". The most common tauopathy is Alzheimer's disease (AD), a dementia characterized by numerous neurofibrillary tangles (NFTs) composed of tau filaments as well as A-Beta senile plaques (Sps). AD is usually sporadic, but familial AD (FAD) is caused by mutations in the amyloid precursor protein (APP), presenilin 1 or 2 genes of some kindreds. However, FAD-like disorders as well as hereditary frontotemporal dementia and Parkinsonism syndromes have been linked to chromosome 17q21-22, and are known collectively as FTDP-17. Fibrillary inclusions composed of hyperphosphorylated tau are the neuropathological hallmarks of FTDP-17, and >10 different pathogenic tau gene mutations have been identified in >20 FTDP-17 kindreds, including some rnis-diagnosed as FAD. Thus, filamentous tau inclusions may play a role in the onset and progression of FTDP-17, and the applicant s preliminary data suggest that different FTDP-17 mutations impair different tau functions or induce gains of toxic properties in tau isoforms leading to phenotypic heterogeneity in FTDP-17 syndromes. To test the hypothesis that tau abnormalities are implicated in mechanisms of brain degeneration in FTDP-17 and related tauopathies, the aims of project 4 are to: 1) develop transgenic (TG) mice that overexpress human wild type (WT) or FTDP-17 mutant tau using transgenes driven by promoters that induce tau pathologies in neurons or glia, 2) cross-breed these TG mice with neurofilament (NF) """"""""knock-out"""""""" mice to induce neuronal tau pathologies without associated NFs, 3) inject adenovirus encoding WT, constitutively active and inactive glycogen synthase kinase 3p (GSK30) into the brains of tau TG mice to determine if GSK30 hyperphosphorylates tau and induces filamentous tau inclusions, 4) assess the effects of intraneuronal tau inclusions on microtubules (MTs) and axonal transport in tau TG mice, 5) determine if and how neurons and glia with filamentous tau inclusions degenerate in their TG mouse models. These studies will elucidate the role of tau pathologies in FTDP-17, AD, and related neurodegenerative tauopathies.
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