The molecular link between beta- and gamma-secretase activity on the amyloid beta precursor protein.
Alzheimer's disease (AD) is characterized by an accumulation in the brain of amyloid beta peptides (Abeta). The production of Abeta requires two sequential cleavages induced by beta- and gamma-secretases on the beta-amyloid precursor protein (APP). Altered activity of these secretases is involved in the pathogenesis of AD. The expression and activity of beta-secretase (BACE1) is augmented in the brain in late-onset sporadic AD. Mutant presenilin 1 (PS1), the major genetic defect of early-onset familial AD (FAD), alters the activity of gamma-secretase, leading to increased production of Abeta42. Here we review the role of oxidative stress as a molecular link between the beta- and the gamma-secretase activities, and provide a mechanistic explanation of the pathogenesis of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying PS1 mutations.
Tabaton
M
M
Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Via De Toni 2, 16132, Genoa, Italy. mtabaton@neurologia.unige.it
Tamagno
E
E
D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000502:physiology; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D053763:Presenilins / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human