Alzheimer's disease is characterized by progressive mental deterioration first manifested by memory loss; post-mortem specimens exhibit neuritic amyloid plaques and neurofibrillary tangles in the central nervous system. All familial Alzheimer's disease mutations studied to date involve the amyloid precursor protein (APP) processing, whose cleavage products include Abeta (Abeta), the major component of neuritic plaque cores. How Abeta participates in the pathophysiology of Alzheimer's disease is unknown. Based on transgenic mouse studies and data produced in the Malinow laboratory, Abeta causes synaptic changes before plaques or tangles become apparent. Using an in vitro model of Alzheimer's disease by transfecting organotypic hippocampal slices, over-expression of APP causes a post-synaptic alteration in AMPA receptor function. Using electrophysiologically-tagged AMPA receptors (AMPA-R), 2 photon laser scanning microscopy and immunofluorescence, this proposal will study the mechanisms underlying this synaptic depression, specifically AMPA-R trafficking, and the resultant Alzheimer's disease pathology.
