Role of the beta-amyloid protein in Alzheimer's disease

A major histopathological hallmark of Alzheimer's disease (AD) is the presence of amyloid deposits in the parenchyma of the amygdala, hippocampus, and neocortex. The principal component of amyloid is the beta-amyloid protein (A beta), a 39-43 amino acid peptide composed of a portion of the transmembrane domain and the extracellular domain of the amyloid precursor protein (APP). APP occurs as several A beta-containing isoforms of 695, 751, and 770 amino acids, with the latter two APP containing a domain that shares structural and functional homologies with Kunitz serine protease inhibitors. In cultured cells, APP mature through the constitutive secretory pathway, and some cell surface-bound APP are cleaved by an enzyme, designated as alpha-secretase, within the A beta domain, an event that precludes A beta amyloidogenesis. Several studies have delineated two additional pathways of APP processing: first, an endosomal/lysosomal pathway generates a complex set of APP-related membrane-bound fragments, some of which contain the entire A beta sequence; and, second, by mechanisms which are not fully understood, A beta 1-40 is secreted into the conditioned medium in vitro and is present in cerebrospinal fluid in vivo. The intracellular sites of enzymes responsible for proteolytic cleavage at the NH2 and COOH termini of A beta, termed gamma- and beta-secretase, respectively, have not been identified. Finally, recent molecular genetic investigations have identified a variety of mutations in APP that segregate with early-onset familial AD and with hereditary cerebral hemorrhage with amyloid, Dutch type (HCHWA-D). Several of these mutations appear to influence APP processing and result in the production of higher levels or longer A beta-related peptides that are inherently more fibrillogenic. Although a variety of lines of evidence implicates APP/A beta in AD, the mechanisms by which A beta influences the biology and vulnerability of neural cells are not fully understood but are very active areas of investigation. This review focuses on the present state of our understanding of APP and A beta in the context of AD.