title: The molecular link between beta- and gamma-secretase activity on the amyloid beta precursor protein.
abstract: 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.
authors.affiliation: Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Via De Toni 2, 16132, Genoa, Italy. mtabaton@neurologia.unige.it
authors.forename: M
authors.initials: M
authors.lastname: Tabaton
authors.forename: E
authors.initials: E
authors.lastname: Tamagno
mesh_terms: 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
chemical_list: D016564:Amyloid beta-Protein Precursor; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human