Abstract
Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid fibrils composed of the amyloid β-protein (Aβ) in senile plaques. Ab is derived from the β-amyloid precursor protein (APP) after β- and γ-secretase cleavages. β-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 γ-secretase will require reconstituting its activity in vitro, mounting evidence suggests that γ-secretase is an unusual intramembrane-cleaving aspartyl protease. Two intramembranous aspartate residues in presenilin (PS) are absolutely required for Aβ generation. Three classes of γ-secretase inhibitors can directly bind to PS, strongly supporting the hypothesis of PS1 as γ-secretase. These results provide the molecular basis for therapeutic interventions that reduce Aβ accumulation in AD patients by inhibiting β- or γ-secretase.
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Xia, W. Amyloid metabolism and secretases in Alzheimer’s disease. Curr Neurol Neurosci Rep 1, 422–427 (2001). https://doi.org/10.1007/s11910-001-0101-z
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DOI: https://doi.org/10.1007/s11910-001-0101-z