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
Current Alzheimer Research
Title:Age-Related Mitochondrial Alterations without Neuronal Loss in the Hippocampus of a Transgenic Model of Alzheimer's Disease
Volume: 10 Issue: 4
Author(s): Mar Cuadrado-Tejedor, Jesus Felipe Cabodevilla, Marta Zamarbide, Teresa Gomez-Isla, Rafael Franco and Alberto Perez-Mediavilla
Affiliation:
Keywords: Alzheimer's disease, early changes, hippocampus, mitochondrial dysfunction, neuronal loss, neurodegeneration, proteome, transgenic mouse, Tg2576
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.
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Cuadrado-Tejedor Mar, Felipe Cabodevilla Jesus, Zamarbide Marta, Gomez-Isla Teresa, Franco Rafael and Perez-Mediavilla Alberto, Age-Related Mitochondrial Alterations without Neuronal Loss in the Hippocampus of a Transgenic Model of Alzheimer's Disease, Current Alzheimer Research 2013; 10 (4) . https://dx.doi.org/10.2174/1567205011310040005
DOI https://dx.doi.org/10.2174/1567205011310040005 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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