PATHOBIOLOGY OF NEURODEGENERATIVE DISEASES LINKED TO TAU GENE MUTATIONS

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Alzheimer's disease (AD) and other neurodegenerative disorders including Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and some cases of frontal temporal dementia (FTD) are characterized histopathologically by inclusions in cerebral neurons and glia. The inclusions consists of microtubule associated protein, tau. In contrast to normal brain tau, which is a soluble protein capable of promoting the polymerization of tubu7lin to form microtubules (MT) and of stabilization of MT, tau in inclusions is in filamentous form. The mechanism(s) involved in formation of tau polymers remains to be elucidated. Recent genetic studies have linked tau mutations to a number of FTD with parkinsonism (FTDP-17) as the cause of taopathy. Several missence mutations (e.g. G272V, N279K, P301L, V337M and R406W) and mutations in the 5 splice site of exon 10, which encodes the second tandem repeat, have been identified. The latter mutations result in an increase of the ratio of four to three repeat tau. Whether the presence of mutant tau or the presence of an abnormal proportion of four and three repeat tau us sufficient for neuron and/or glia to form tau inclusion remains unclear at present. Moreover, it remains unclear if the function of tau is compromised by these mutations, iv various mutations have different effects, or if these mutations alter the susceptibility of neurons to degeneration. To examine these issues focusing on mutants identified in FTDP-17, (ii0 determine if mutant and wild type tau differ in polymerization potential, susceptibility to proteolysis and other physico-chemical properties, (iii) study the response of cultured cells and mutation in tau gene as well as tau in transgenic animals generated by Projects 3 and 4, and (v) study neuronal and glial cultures of transgenic animals and determine if cells from mice with mutant tau differ from those will wild type tau in response to (a) microtubule destabilizing agent colchicine, (b) phosphatase inhibitors, and (c) oxidant stress.