The abnormal accumulation of tau within the somatic dendritic compartment of neurons in Alzheimer's disease (AD) and other tauopathies is a hallmark neuropathologic lesion linked by still unknown mechanisms to neurodegeneration. Pathologic tau accumulation is likely to be related, in large part, to tau's posttranslational fate, but remarkably little is known about tau turnover or axonal transport in either normal neurons or in neuropathologic states. Moreover, adverse consequences of tau accumulation may well include secondary impairments of transport and activation of proteases leading to neurodegeneration. The overall goal of this proposal will be to provide fundamental information about the posttranslational behavior of tau by systematically analyzing the consequences of wild-type tau overexpression in neurons on axonal transport and on major proteolytic systems that may metabolize tau. These studies will specifically test the hypotheses that age-dependent alterations of tau proteolysis or axonal transport contribute to tau accumulation and that abnormal, proteolytic responses to tau accumulation/dysfunction promote neurodegeneration. To achieve these goals, we propose to: 1) evaluate the competency of the mechanisms for slow transport and fast transport, including tau transport, in wild-type mice and in a mouse model of tau-related neurodegeneration, which exhibits age-related tau accumulation and cell loss, before and after the onset of tau pathology and neurodegeneration; 2) assess the function of three major proteolytic systems potentially involved in tau turnover, the calpain-calpastatin, proteasome, and endosomal/lysosomal/autophagic systems, in normal and human tau transgenic mice; 3) confirm the role of specific proteolytic systems in tau turnover in neuronal cells and in pathologic tau accumulation in human tau transgenic mice in vivo. As time permits, we will also investigate effects on axonal transport and proteolysis after superimposing an amyloid-b burden on htau mice.
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