Alzheimer's disease (AD) is a progressive neurodegenerative dementing disorder affecting over 3.5 million Americans for which there is not known effective therapy. Genetic, cell culture, and animal studies support a key role of the amyloid precursor protein (APP) and amyloid beta protein (alpha beta) in the pathogenesis of AD, and related disorder, congophilic amyloid angiopathy (CAA). The applicant proposes to study two existing transgenic mouse models of cerebral amyloid deposition and to contribute the development of a transgenic model of vascular APP production to examine specific hypotheses relevant to the pathophysiology and neuropathology of AD and CAA. The objective of this Mentored Clinical Scientist proposal is to study whether APP transgene expression and/or Abeta deposition is associated with neuronal loss, vascular damage, synaptic alterations, gliotic changes, or loss of functional integrity of neural systems. Stereologically based statistically unbiased techniques will be used to assess neuronal counts, amyloid burden, and vascular amyloid in the entorhinal cortex, cingulate cortex, and hippocampal subfields to transgenic mice an non-transgenic littermate controls. The regional distribution and morphology of amyloid plaques will be analyzed immunohistochemically with light and confocal microscopy. The relation of transgene APP splice form expression to Abeta deposition will be assessed through in situ hybridization. Functional integrity of neural systems will be evaluated by cytochrome oxidase histochemistry and in situ hybridization, and synaptic integrity will be evaluated by immunohistochemistry and in situ hybridization. The applicant proposes to assess the effects of APP over-expression in vascular smooth muscle by producing and evaluating a new transgenic model of cerebral amyloid angiopathy. The candidate is a board certified neurologist who has completed two productive years of fellowship training in the well established neuroscience laboratory of Bradley T. Hyman. The laboratory includes experience and facilities for stereological techniques, molecular biology, immunohistochemistry, and confocal microscopy as well as access to human pathological specimens through the Alzheimer Disease Research Center. The additional basic science training in an exciting and novel project with direct clinical relevance will allow the candidate to develop into an independent academic neuroscientist.
