Age-Related Mitochondrial Alterations without Neuronal Loss in the Hippocampus of a Transgenic Model of Alzheimer's Disease

Author(s): Mar Cuadrado-Tejedor, Jesus Felipe Cabodevilla, Marta Zamarbide, Teresa Gomez-Isla, Rafael Franco, Alberto Perez-Mediavilla.

Journal Name: Current Alzheimer Research

Volume 10 , Issue 4 , 2013

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Abstract:

The Tg2576 mouse, which carries the Swedish mutant form of human β-amyloid precursor protein (hAPPswe), 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 hAPPswe. 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.

Keywords: Alzheimer's disease, early changes, hippocampus, mitochondrial dysfunction, neuronal loss, neurodegeneration, proteome, transgenic mouse, Tg2576

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Article Details

VOLUME: 10
ISSUE: 4
Year: 2013
Page: [390 - 405]
Pages: 16
DOI: 10.2174/1567205011310040005
Price: $58

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