S4–01–01: Seeded initiation and spread of aggregated beta‐amyloid

The deposition of beta-amyloid is inducible in the brains of susceptible hosts by seeds consisting of aggregated beta-amyloid. Current evidence favors the view that the corruptive templating of beta-amyloid is similar to the process by which prions convey their pathogenic structural features to naïve prion protein molecules. In Alzheimer's disease, the proteinaceous lesions appear to arise endogenously and then spread systematically to other brain areas. beta-amyloid seeds thus are a potential vector for the amplification of proteinaceous aggregates in vivo. The cellular mechanisms by which beta-amyloid seeds travel from one place to another remain poorly understood. Using an established exogenous seeding paradigm, beta-amyloid-rich brain extracts were infused into the hippocampal formation or neocortex of APP-transgenic rodents. The temporal and spatial disposition of the seeds and of the subsequently induced deposits were analyzed. The local pattern of exogenously seeded beta-amyloid deposition is governed to a considerable extent by simple diffusion of the injected brain extract. When beta-amyloid deposition is focally induced by beta-amyloid seeds in one brain region, other areas are subsequently beset by beta-amyloid aggregates. The secondarily affected areas contain extracellular deposits (which generally emerge systematically in axonally interconnected regions) and/or vascular deposits (cerebral amyloid angiopathy). Beta-amyloid deposition can be seeded in the brains of transgenic rodents by beta-amyloid-rich brain extracts. Once the seeding of beta-amyloid has been initiated, cellular (and possibly vascular) mechanisms promote the continued ramification of beta-amyloid aggregation at distal sites. Key Collaborators: Amarallys Cintron, Rebecca Rosen, Harry LeVine III, and Mathias Jucker and colleagues in Tübingen, Germany.