PMID: 11898552Mar 20, 2002Paper

Amyloid metabolism and secretases in Alzheimer's disease

Current Neurology and Neuroscience Reports
W Xia

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.

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Citations

Nov 26, 2002·Trends in Neurosciences·Frédéric Checler, Bruno Vincent
Sep 18, 2015·Neural Plasticity·Jean-Pascal MorinFederico Bermudez-Rattoni
Jan 17, 2012·Proteomics·Bart H J van den Berg, Andreas Tholey
Oct 7, 2015·Molecular Neurodegeneration·Manasi MalikSteven Estus
Mar 2, 2006·The Journal of Biological Chemistry·Henrik ZetterbergWeiming Xia
Jun 23, 2004·Neurobiology of Disease·Peter J MorinKenneth S Kosik
Dec 21, 2005·Journal of Neuroscience Methods·Tianming LiuStephen T C Wong

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