Amyloid metabolism and secretases in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid fibrils composed of the amyloid beta-protein (A beta) in senile plaques. A beta is derived from the beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavages. beta-secretase was recently identified to be a membrane-anchored aspartyl protease that is widely distributed in subcellular compartments, including Golgi, trans-Golgi network, and endosomes. Although definitive identification of gamma-secretase will require reconstituting its activity in vitro, mounting evidence suggests that gamma-secretase is an unusual intramembrane-cleaving aspartyl protease. Two intramembranous aspartate residues in presenilin (PS) are absolutely required for A beta generation. Three classes of gamma-secretase inhibitors can directly bind to PS, strongly supporting the hypothesis of PSI as gamma-secretase. These results provide the molecular basis for therapeutic interventions that reduce A beta accumulation in AD patients by inhibiting beta- or gamma-secretase.