ALZHEIMERS-DISEASE AMYLOID PRECURSOR PROTEIN (A-BETA-PP) - PROTEOLYTIC PROCESSING, SECRETASES AND BETA-A4 AMYLOID PRODUCTION

The major component of Alzheimer's disease amyloid is the 4 kDa peptide beta A4 which is produced from an integral membrane protein (amyloid beta precursor protein, A beta PP) by proteolytic processing. Cleavage of the beta A4 domain from the precursor protein is part of a complex process which results in the release of A beta PP from the membrane. A beta PP is released by cleavage within the beta A4 domain by a putative alpha-secretase. However, other cleavage sites cist, one of them Being located at the NH2-terminus of beta A4. Several factors such as genetic mutations within or near the beta A4 domain, inappropriate production of A beta PP isoforms, increased A beta PP synthesis, or alterations in A beta PP trafficking seem to favor this ''amyloidogenic'' cleavage which is due to beta-secretase activity. A major determining event in the production of beta A4 amyloidogenic species appears to be the COOH-terminal cleavage, due to gamma-secretase activity This generates species either of 39/40 residues or longer species of 42/43/44 residues which have a greater tendency to aggregate. A central focus of current research is to elucidate the cellular trafficking and targeting of A beta PP in order to understand how the various proteolytic systems operate and are selected This could lead to the development of therapeutic agents which control the formation, aggregation or mobilization of cerebral amyloid in Alzheimer's disease.