The amyloid-beta peptide (am-beta) is a major constituent of the amyloid deposits associated with presenile dementia in Alzheimer's disease (AD) and Down's syndrome. This peptide is apparently generated by abnormal proteolytic processing of the amyloid precursor polypeptide (APP) and recent studies have demonstrated the importance of intracellular catabolism in determining the fate of am-beta and APP. Several other recent studies have suggested the possibility that am-beta mediates biological activities, such as neurotrophic/neurotoxic effects. We have recently demonstrated that am-beta is recognized by the SEC receptor, a receptor originally identified by its recognition of alpha1-antitrypsin (alpha1 AT)-elastase and several other serpin-enzyme complexes. The SEC receptor mediates endocytosis and intracellular catabolism of its ligands and is probably responsible for clearance/catabolism of its ligands in vivo. The SEC receptor also mediates several biological activities, including neutrophil chemotaxis, and determines the balance of elastase and anti-elastase activities in the pericellular milieu by signalling for increases in synthesis of alpha1 AT. In this application, we present preliminary evidence that the SEC receptor mediates endocytosis and intracellular catabolism of am-beta, that am-beta mediates neutrophil chemotaxis through the SEC receptor and that the SEC receptor is expressed on cells which may be relevant to the pathophysiology of AD, including cells of neuronal origin, cells of myeloid origin, and platelets. Moreover, we present preliminary evidence that the SEC receptor mediates chemotaxis of glial cells. We propose to study the structure and function of the SEC receptor, its expression in cells from the CNS, its role in the chemotaxis of glial and neuronal cells toward am-beta and its role in catabolism of am-beta. Ultimately these studies may be applicable to secondary pathophysiologic events in AD and Down's syndrome and to establishment of a target for novel therapeutic approaches to dementia in these conditions.
| Mazziotti, M; Perlmutter, D H (1998) Resistance to the apoptotic effect of aggregated amyloid-beta peptide in several different cell types including neuronal- and hepatoma-derived cell lines. Biochem J 332 ( Pt 2):517-24 |
| Boland, K; Behrens, M; Choi, D et al. (1996) The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta peptide but not aggregated, cytotoxic amyloid-beta peptide. J Biol Chem 271:18032-44 |
| Boland, K; Manias, K; Perlmutter, D H (1995) Specificity in recognition of amyloid-beta peptide by the serpin-enzyme complex receptor in hepatoma cells and neuronal cells. J Biol Chem 270:28022-8 |
