Deposition of fibrillar amyloid-␤ protein (A␤) in senile plaques and in the walls of cerebral blood vessels is a key pathological feature of Alzheimer's disease and certain related disorders. Fibrillar A␤ deposition is intimately associated with neuronal and cerebrovascular cell death both in vivo and in vitro. Similarly, accumulation of the A␤ protein precursor (A␤PP) is also observed at sites of fibrillar A␤ deposition. Recently, we reported that fibrillar A␤, but not unassembled A␤, promotes

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... the specific binding of A␤PP through its cysteine-rich, amino-terminal region (Melchor, J. P., and Van Nostrand, W. E. (2000) J. Biol. Chem. 275, 9782-9791). In the present study we sought to determine the precise site on A␤PP that facilitates its binding to fibrillar A␤. A series of synthesized overlapping peptides spanning the cysteine-rich, amino-terminal region of A␤PP were used as competitors for A␤PP binding to fibrillar A␤. A peptide spanning residues 105-119 of A␤PP competitively inhibited A␤PP binding to fibrillar A␤ in a solid-phase binding assay and on the surface of cultured human cerebrovascular smooth muscle cells. Alanine-scanning mutagenesis of residues 105-117 within glutathione Stransferase (GST)-A␤PP-(18 -119) revealed that His 110 , Val 112 , and Ile 113 are key residues that facilitate A␤PP binding to fibrillar A␤. These specific residues belong to a common ␤-strand within this region of A␤PP. Wildtype GST-A␤PP-(18 -119) protected cultured human cerebrovascular smooth muscle cells from A␤-induced toxicity whereas H110A mutant GST-A␤PP-(18 -119) did not. Wild-type GST-A␤PP-(18 -119) bound to different isoforms of fibrillar A␤ and fibrillar amylin peptides whereas H110A mutant and I113A mutant GST-A␤PP-(18 -119) were substantially less efficient binding to each fibrillar peptide. We conclude that His 110 , Val 112 , and Ile 113 , residing in a common ␤-strand region within A␤PP- (18 -119) , comprise a domain that mediates the binding of A␤PP to fibrillar peptides.