Amyloid metabolism and secretases in Alzheimer's disease
Abstract
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.
References
Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein
The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain
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