Tau protein is a neuronal microtubule associated protein that promotes microtubule assembly and functions in axonal development. Additionally, abnormally phosphorylated tau is an integral component of neurofibrillary tangles and thus may contribute to Alzheimer's disease pathogenesis. While much is known about the structure and function of tau in microtubule assembly, the mechanisms that govern tau's spatial localization and that regulate tau phosphorylation, and thus its activity, are poorly understood. The applicant has determined that in transfected neuronal cells, the amino terminal of tau localizes to the cell membrane and creates a dominant negative effect on neurite outgrowth. She hypothesizes that tau mediates microtubule-membrane interactions that are required for neuritic development. Here she proposes to test this hypothesis. The molecular basis for tau's association with the membrane will be elucidated and the significance of this association in neuronal differentiation will be determined. To determine the molecular basis of tau's association with the membrane, the applicant will 1) identify the area of the amino terminus of tau that binds to the membrane, 2) determine the biochemical characteristics of the binding between tau and purified membrane, and 3) identify the component(s) of the membrane that interact with tau using co-immunoprecipitation. To investigate the role of membrane associated tau during neuronal differentiation, she will 1) examine membrane associated tau in non-transfected differentiated neuronal cells and in primary cultured neurons and 2) investigate the effect of over expressing the membrane associated tau domain during neuronal differentiation. These studies will provide new insights into the function of tau's amino terminus and into tau's role in the transduction of extracellular signals to the cytoskeleton.
