STRUCTURAL ASPECTS OF ABPP FUNCTION AND PATHOLOGY

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The long-term objective of the laboratory is a detailed characterization of the structure and the function of the Alzheimer's amyloid beta protein precursor (ABPP). Besides being implicated in Alzheimer's disease, this protein has recently been found in platelets, and a mutant version of the beta peptide itself has been linked to a hereditary cerebral hemorrhage, HCHWA-D. A description of the functional (or dysfunctional) behavior of ABPP in normal and pathological states might suggest new therapeutic approaches to the treatment of neurodegenerative diseases such as Aizheimers as well as cardiovascular disorders such as stroke. With these objectives in mind, the thrust of our proposed research is two-fold: a) to derive further high-resolution structural information about ABPP which might yield insights into function; and b) use the structural information that we already have to try to identify proteins in the brain and in the blood that specifically interact with ABPP or its subfragments. Our specific aims for the term of the grant are: 1. To begin a comprehensive study of the structure and function of ABPP by conducting a high resolution "alanine scan" of the N-terminal domain. 2. To produce large quantities of purified, recombinant ABPP N-terminal domain for structural studies by X-ray crystallography and multidimensional NMR. 3. To study the possible role of beta amyloid fibrils as stimulators of human tissue plasminogen activator. 4. To isolate molecular clones of cognate proteases or esterases that bind to the ABPP Kunitz domain. This work, if successful, should start to bring into focus the network of proteins in the body, both in the brain and in the blood, that interact with ABPP. This information will help elucidate the role ABPP plays both in healthy and in diseased tissue.