Proteolytic processing of Alzheimer’s disease associated proteins

Amyloid β-peptide (Aβ), the major component of senile plaques, is generated by proteolytic processing from the β-amyloid precursor protein (βAPP). Mutations within the βAPP gene cause early onset familial AD (FAD) by affecting Aβ generation. Interestingly, the much more abundant mutations within the presenilin (PS) genes also result in the abnormal generation of a 42 residue Aβ (Aβ42), thus clearly supporting a pivotal role of Aβ for the pathology of AD. PS proteins are proteolytically processed into stable 30kDa N-terminal fragments (NTF) and 20kDa C-terminal fragments (CTF). Beside the conventional proteolytic pathway, PS proteins can also be cleaved further 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 Aβ42 generation and intracellular accumulation. Using Caenorhabditis elegans as a simple animal model, we demonstrate that PS proteins are involved in NOTCH signaling. FAD causing mutations interfere with the biological function of PS proteins in NOTCH signaling.