title: Estrogens stabilize mitochondrial function and protect neural cells against the pro-apoptotic action of mutant presenilin-1.
abstract: Mutations in presenilin-1 (PS-1) account for approximately half the cases of autosomal dominant early-onset Alzheimer's disease (AD). Recent data indicate that PS-1 mutations may render neurons vulnerable to apoptosis induced by various insults. We now report that 17beta-estradiol, which appears to reduce the risk of sporadic AD, protects cultured PC12 cells expressing mutant PS-1 against apoptosis induced by trophic factor withdrawal (TFW) and exposure to amyloid beta-peptide 25-35 (Abeta). Estriol also provided significant protection against apoptosis induced by TFW and Abeta, whereas corticosterone was ineffective. 17beta-Estradiol prevented decreases in mitochondrial transmembrane potential and energy charge/redox state following exposure of cells to TFW and Abeta in control cell lines and lines expressing mutant PS-1, suggesting an action in the apoptotic pathway upstream of mitochondrial alterations. Abeta caused an increase in mitochondrial reactive oxygen species which was enhanced by mutant PS-1, and suppressed by 17beta-estradiol. The ability of 17beta-estradiol to preserve mitochondrial function, suppress oxidative stress, and counteract the pro-apoptotic actions of mutant PS-1 suggests a generalized neuroprotective action of estrogens in both sporadic and inherited forms of AD.
authors.affiliation: Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
authors.forename: N
authors.initials: N
authors.lastname: Robinson
authors.forename: Q
authors.initials: Q
authors.lastname: Guo
mesh_terms: D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation; D003345:Corticosterone / Q000494:pharmacology; D004734:Energy Metabolism; D004958:Estradiol / Q000494:pharmacology*; D004964:Estriol / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology; D017354:Point Mutation; D053764:Presenilin-1; D051381:Rats; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D006133:Growth Substances; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C074636:amyloid beta-protein (25-35); D004958:Estradiol; D004964:Estriol; D003345:Corticosterone