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:Cellular and Molecular Neuropharmacology Laboratory. CIMA. University of Navarra. Avda. Pio XII, 55. 31008 Pamplona. Spain.
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.
