title: Age-related mitochondrial alterations without neuronal loss in the hippocampus of a transgenic model of Alzheimer's disease.
abstract: The Tg2576 mouse, which carries the Swedish mutant form of human β-amyloid precursor protein (hAPP(swe)), develops Alzheimer's Disease (AD)-like phenotype (synaptic pathology, cognitive impairment and β amyloid -Aβ- plaques.) in the absence of significant neuronal loss. We have analyzed the hippocampal proteome of Tg2576, focusing on changes at 7 months of age, when Aβ levels begin to increase but cognitive symptoms are still not evident, and at 16 months, when most AD-like features are manifested. Proteins differentially expressed with respect to wild-type animals were grouped according to their biological function and assessed in the context of AD. Metabolic enzymes, propionyl- CoA carboxylase, which has not been previously related to AD, and glutamine synthetase, which is a key enzyme for ammonium removal, were among deregulated proteins. Mitochondria of young animals have to cope with the metabolic stress and elevated ATP demand caused by overexpression of hAPP(swe). Significantly, a large number of mitochondrial proteins (16, 28% of the total) were deregulated in young Tg2576 mice and seven of them were found at normal levels in aged animals. Mitochondrial dysfunction in 7-month-old mice was confirmed by reduction in the inner membrane integrity and increase in the activity of cytochrome c oxidase. The proteome analysis indicates that mitochondrial and overlapping metabolic alterations are adaptive upon aging, and may explain the synaptic pathology and cognitive impairment in the absence of neuronal loss. Animal models such as 7-month-old Tg2576 mice and tools to investigate synaptic alterations before appearance of neuronal death may help in understanding the pathological mechanisms occurring at early stages of AD.
authors.affiliation: Cellular and Molecular Neuropharmacology Laboratory. CIMA. University of Navarra. Avda. Pio XII, 55. 31008 Pamplona. Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Cuadrado-Tejedor
authors.forename: Jesús Felipe
authors.initials: JF
authors.lastname: Cabodevilla
authors.forename: Marta
authors.initials: M
authors.lastname: Zamarbide
authors.forename: Teresa
authors.initials: T
authors.lastname: Gómez-Isla
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.forename: Alberto
authors.initials: A
authors.lastname: Perez-Mediavilla
mesh_terms: D000367:Age Factors; D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D006624:Hippocampus / Q000473:pathology* / Q000648:ultrastructure*; D006801:Humans; D007525:Isoelectric Focusing; D013058:Mass Spectrometry; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000473:pathology; D009154:Mutation / Q000235:genetics; D060066:Protein Interaction Maps; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003576:Electron Transport Complex IV