PROJECT SUMMARY Proteostasis dysfunction of pancreatic β-cells results in accumulation of oligomerized amylin within pancreatic islets, which is a hallmark of type-2 diabetes. We recently showed that oligomerized amylin also incorporates into the brain blood vessel walls, forms neuritic deposits and co-localizes with Alzheimer's disease (AD) β-amyloid peptides (Aβ) as mixed Aβ-amylin plaques in brains of individuals with late-onset AD as well as familial early-onset AD. It is unknown whether cerebral amylin deposits are a consequence of AD or type-2 diabetes, or a “hidden” trigger of AD. Moreover, we found that overexpressing human amylin within pancreatic islets in rats induces systemic amylin dyshomeostasis, brain amylin accumulation, microglia activation and behavior changes. Furthermore, elevated human amylin in the periphery greatly accelerates behavior changes in a rat model of AD pathogenesis. These findings suggest the hypothesis that amylin dyshomeostasis in pancreatic islets and subsequent secretion of oligomerized amylin in the blood can affect the progression of AD by compromising the ability of microglia to efficiently clear Aβ and by inducing mixed Aβ-amylin pathology. Thus, ameliorating amylin dyshomeostasis in the periphery can limit the progression of AD. The overarching goal of this proposal is to test our hypothesis and investigate molecular mechanisms underlying the interaction of amylin with Aβ pathology. We will accomplish this goal by characterizing novel transgenic mice with inducible and reversible expression of human amylin in the pancreas (HuAmy line). We will carefully dissect proteostasis dysfunction of pancreatic β-cells in the periphery and the consequent liability it imposes on the central nervous system. We will also cross HuAmy line and 85Dbo line to generate APP/PS1 transgenic mice with regulated expression of human amylin in the periphery. We predict that turning off the human amylin transgene expression at early time points during aging mitigates the disease progression in HuAmy:APP/PS1 mice by limiting the blood-brain barrier injury and rescuing the ability of microglia to clear Aβ. This investigation using novel regulated amylin expression represents the most direct in vivo approach to rigorously test the involvement of peripheral amylin in the biological pathways of AD pathogenesis. The completion of these aims will elucidate the interplay of amylin dyshomeostasis with the progression of Aβ pathology and whether ameliorating amylin dyshomeostasis in the periphery can reduce or reverse AD in a preclinical model. We believe that the proposed investigation fills significant gaps in our understanding of the molecular link between type-2 diabetes and AD.