Mechanisms of amyloid-beta clearance.

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EXCEED THE SPACE PROVIDED. Transgenic mouse models over-expressing APP develop senile plaques in an age-dependent fashion similar to those found in patients with Alzheimer's disease (AD). Recent evidence shows that active or passive immunotherapy dramatically prevents amyloid-13 deposition in transgenic mice. Clearance of existing amyloid-13 deposits present in Alzheimer's disease patients, in addition to prevention of new plaque formation, will be critical for an effective treatment. Observing senile plaques before and after treatment is the only direct way to measure clearance of existing deposits, but until recently this has not been possible. We have developed novel multiphoton microscopy techniques that allow longitudinal in vivo imaging of individual plaques. Using this approach, we demonstrated clearance of existing plaques in transgenic mice 3-5 days after a single application of antibodies to the cortex. In this application, we propose to test hypotheses about the mechanism of clearance. Aim 1 follows from our observation that clearance can also occur with addition of F(ab')2 fragments, suggesting that Fc-mediated mechanisms are not necessary. We propose a model whereby clearance results from a two-step process involving disaggregation of amyloid-13 deposits via direct biophysical interaction followed by active removal of the amyloid. Aim 2 asks whether systemic immunization, rather than topical application of antibody to cortex, will lead to clearance; if so, we will determine necessary titers and optimal epitopes. Aim 3 takes advantage of in vitro results from several laboratories demonstrating that amyloid-13 binding compounds prevent or reverse formation of amyloid fibrils. We will test whether they are disaggregating agents in vivo. The results will strongly impact the development of treatments aimed at removing senile plaques and the associated neurological damage in Alzheimer's disease. PERFORMANCE SITE ========================================Section End===========================================