Biochemical, genetic, and epidemiological evidence indicates that inflammation is an essential part of the pathogenesis of Alzheimer's disease. Over the last decade of this grant, we have focused on the role that specific inflammatory molecules play in the Alzheimer's pathogenic pathway. We have learned, from both in vivo and in vitro experiments in our and other labs, that several acute phase/inflammatory molecules in the brain, specifically anti-chymotrypsin (ACT) (ACT) and apolipoprotein E (apoE) can promote the formation of the neurotoxic amyloid deposits that are the main pathological hallmark of the disease. They do this by binding directing to the Abeta peptide and promoting its polymerization into amyloid filaments. Furthermore, ACT is greatly overproduced in affected areas of the AD brain, providing a potential mechanism by which the regional specificity of amyloid deposition can be explained. ACT over- expression is evidently caused by activation of ACT mRNA synthesis in astrocytes by the inflammatory cytokine IL-1 released from activated microglia. ApoE was recently found to also be over expressed in affected areas of AD brain, but the mechanism is not yet known. We have extended this inflammatory cascade to include the amyloid precursor protein (APP) itself, by finding that IL-1 up-regulates the production of APP in astrocytes, but at the translational rather than the transcriptional level. We propose to extend this findings in order to solidify and clarify the role of ACT and apoE in AD. Specifically, we will test the hypothesis that ACT and apoE directly affect amyloid formation in vivo. TO this end, we have created a transgenic mouse line that expresses human ACT in astrocytes and will use it alone, or together with apoE and over- expression of APP. We will identify aspects of the interaction between Abeta and the """"""""pathological chaperones"""""""" ACT and apoE, and use this information to develop peptide inhibitors of the interactions that may form the basis for the development of therapeutic compounds to slow or prevent neurotoxic amyloid formation. Such blocking peptides will be introduced by several means into the transgenic mice to determine their ability to reduce the level of amyloid formation.
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