The overall goal of this project is to understand how the expression of proteins important in Alzheimer's disease is controlled in the brain and how that control is altered in the disease state. The identification of the two protein components (alpha-1-antichymotrypsin and the Beta-protein) of the neuropathological amyloid deposits in Alzheimer's disease (AD) brain has opened the way of how these molecules come to be expressed. We have found that alpha-1-antichymotrypsin (ACT) is over expressed in those regions of Alzheimer brain affected by the disease, specifically in astrocytes. There are also differences between Alzheimer's disease patients and controls in the levels of the different beta-protein precursor mRNAs, and beta-protein precursor can be shown to be over- expressed in astrocytes in models of brain damage. A protease, Clipsin, that we have purified, is a strong candidate for a cleavage enzyme that can release the beta-protein from its precursor, and is also expressed in brain, probably in mast cells. Thus changes in the expression of two and possibly three proteins characterize AD and may underlie the mechanism of the disease. We wish to discover how the changes in gene expression observed in AD come about and whether they are a direct result of mutation. (25-50 percent of AD cases arise in certain families and appear to be inherited as an autosomal dominant trait.) Specifically, we propose a series of experiments designed to determine (1) the signaling molecules responsible for inducing ACT, beta-protein precursor, and potentially Clipsin expression in cultured cells-astrocytes and mast cells, (2) the DNA sequences in the regulatory region of these genes which respond to the inducing signals, (3) whether over-expression of ACT in transgenic mice can mimic the over-expression in AD and lead to neuropathology, and (4) whether, and how, the gene coding ACT may be mutant in AD, resulting in aberrant expression.
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