Peripheral sequestration of abeta on transport systems

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DESCRIPTION (provided by applicant): The idea of interdependence between peripheral and CNS levels of A/3 in the pathogenesis of Alzheimer's disease is fairly new. The observation that immunotherapy with anti-A/3 antibodies led to a significant increase in peripheral A/3 formed the basis of the peripheral sink hypothesis set forth by Dave Holtzman. Subsequent observations of a peripheral effect on A/3 was shown by our own lab, both for antibody-mediated sequestration and using other peripheral A/3 binding agents (PABBAs) such as gelsolin that does not cross into the brain. Virtually nothing has been published showing the mechanism by which peripheral sequestration works under any experimental paradigm. A/3 can be transferred between the brain and periphery either by passive bulk flow, or by active transport. This proposal aims to examine which of these two systems is impacted by gelsolin-mediated peripheral sequestration, and the dynamic flux of A/3 in specific brain compartments, in the presence, or absence of aggregated amyloid. This work will extend our published observations providing mechanistic evidence that this novel therapeutic approach is worthy of further development, and by identifying which systems are affected, it will direct efforts to new targets that could be developed for clinical use.