PROTEOLYTIC PROCESSING OF ALZHEIMERS-DISEASE ASSOCIATED PROTEINS

Amyloid beta-peptide (A beta), the major component of senile plaques: is generated by proteolytic processing from the beta-amyloid precursor protein (beta APP). Mutations within the beta APP gene cause early on set familial AD (FAD) by affecting A beta generation. Interestingly, t he much more abundant mutations within the presenilin (PS) genes also result in the abnormal generation of a 42 residue A beta (A beta 42), thus clearly supporting a pivotal role of A beta for the pathology of AD. PS proteins are proteolytically processed into stable 30 kDa N-ter minal fragments (NTF) and 20 kDa C-terminal fragments (CTF). Beside th e conventional proteolytic pathway, PS proteins can also be cleaved fu rther C-terminal by proteases of the caspase superfamily. PS proteins were localized within the endoplasmic reticulum (ER) and early Golgi, compartments which we have demonstrated to be involved in A beta 42 ge neration and intracellular accumulation. Using Caenovhabditis elegans as a simple animal model, we demonstrate that PS proteins are involved in NOTCH signaling. FAD causing mutations interfere with the biologic al function of PS proteins in NOTCH signaling.