Intriguing data from other laboratories have shown evidence of acute effects of solubilized P protein and related fragments in vitro and in vivo in the rat brain. As discussed below, it is difficult to assess the physiological significance of these short term effects with solubilized peptides which have never been measured in human brain and how they may relate to the complex, insoluble amyloid deposits known to occur in AD brain. In contrast, we have investigated the long-term fate of Alzheimer's amyloid cores injected into rat hippocampus and observed neuron loss, Alz-50 and ubiquitin immunoreactivity, and amyloid phagocytosis and migration to vessel walls (Preliminary studies). We now propose to extend and refine this work using progressively more complex synthetic amyloid deposits to investigate the role of specific molecular and cellular elements in plaque pathogenesis. In particular, in addition to putative neurotoxic effects, we propose to explore the interaction between synthetic amyloid deposits and heparin binding growth factors and their relationships to cellular elements involved in AD.
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