title: Cytoplasmic gelsolin increases mitochondrial activity and reduces Abeta burden in a mouse model of Alzheimer's disease.
abstract: Accumulation of amyloid-beta (Abeta) peptides is thought to be a critical event in the pathology of Alzheimer's disease (AD), because they induce multiple neurotoxic effects, including mitochondrial dysfunction and apoptotic cell death. Therefore the reduction of Abeta is considered a primary therapeutic target. Gelsolin, an Abeta binding protein, has been shown to inhibit apoptosis, although the underlying mechanism is unclear. To clarify these effects, we manipulated cytoplasmic gelsolin levels through viral-directed overexpression in the brain of APP/Ps1 transgenic mice. We observed that gelsolin reduces brain Abeta burden in the APP/Ps1 mice, possibly by enhancing Abeta clearance via megalin. The reduction in brain Abeta levels was accompanied by an inhibition of nitric oxide production and cell death, not only in the choroid plexus but also in the cerebral cortex. Notably, overexpressed gelsolin restored the impaired mitochondrial activity in the APP/Ps1 mice, resulting in the increase of cytochrome c oxidase activity. By contrast, RNA interference to block gelsolin expression, confirmed that cytoplasmic gelsolin acts as a modulator of brain Abeta levels and its neurotoxic effects. We conclude that gelsolin might prevent brain amyloidosis and Abeta-induced apoptotic mitochondrial changes. These findings make cytoplasmic gelsolin a potential therapeutic strategy in AD.
authors.affiliation: Neuroscience Laboratory, Research Center, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Desiree
authors.initials: D
authors.lastname: Antequera
authors.forename: Teo
authors.initials: T
authors.lastname: Vargas
authors.forename: Cristina
authors.initials: C
authors.lastname: Ugalde
authors.forename: Carlos
authors.initials: C
authors.lastname: Spuch
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Molina
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Felix
authors.initials: F
authors.lastname: Bermejo-Pareja
authors.forename: Eva
authors.initials: E
authors.lastname: Carro
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D002831:Choroid Plexus / Q000166:cytology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D042963:Electron Transport Complex II / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018260:Gelsolin / Q000378:metabolism / Q000494:pharmacology*; D005822:Genetic Vectors / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009245:NADH Dehydrogenase / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D053764:Presenilin-1 / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D014162:Transfection / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018260:Gelsolin; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D042963:Electron Transport Complex II; C511268:SDHA protein, human; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; C118906:NDUFB9 protein, human