The low molecular weight microtubule-associated protein tau has been implicated in a number of neurodegenerative diseases, including Alzheimer's disease, PSP, Pick's disease, frontotemporal dementia with parkinsonism (FTDP), and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam. Together these neurodegenerative diseases are referred to as tauopathies since they share common neuropathological features, including abnormal hyper-phosphorylation and filamentous accumulation of aggregated tau proteins (224). Reports have implicated either alternative RNA splicing (generating different isoforms) or missense mutations as mechanisms underlying many of the tauopathies. Therefore, transgenic mice have been generated that over-express specific splice variants or missense mutation of tau (225). One such transgenic line has been developed to over-express the shortest human tau isoform (226). These mice showed progressive motor weakness, intraneuronal and intra-axonal inclusions (detectable by one-month postnatal), and reduced axonal transport. Fibrillary tau inclusions developed in the neocortical neurons after 18 months of age implicating age-specific processes in the pathogenesis of fibrous tau inclusions. An interesting tau transgenic has been developed in D. melanogaster where expression of a tau missense mutation showed no evidence of large filamentous aggregates (neurofibrillary tangles). However, aged flies showed evidence of vacuolization and degeneration of cortical neurons (227). These observations suggest that tau-mediated neurodegeneration is age-dependent and may take place independent of protein aggregation.
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