Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer's disease.
Brain aging is associated with synaptic decline and synaptic function is highly dependent on mitochondria. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of several neurodegenerative diseases. Here we have investigated the repair of oxidative base damage, in synaptosomes of mouse brain during normal aging and in an AD model. During normal aging, a reduction in the base excision repair (BER) capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of presymptomatic and symptomatic AD mice harboring mutated amyolid precursor protein (APP), Tau, and presinilin-1 (PS1) (3xTgAD). Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed.
Gredilla
Ricardo
R
Danish Center for Molecular Gerontology, Department of Molecular Biology, University of Aarhus, Aarhus, Denmark.
Weissman
Lior
L
Yang
Jenq-Lin
JL
Bohr
Vilhelm A
VA
Stevnsner
Tinna
T
D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000473:pathology*; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology / Q000648:ultrastructure*; D004249:DNA Damage / Q000502:physiology; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D004272:DNA, Mitochondrial; D004195:Disease Models, Animal; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics; D013574:Synaptosomes / Q000473:pathology / Q000502:physiology*; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D004272:DNA, Mitochondrial; D034904:Lamin Type A; C508853:PSEN1 protein, human; D053764:Presenilin-1; C494763:Vdac1 protein, mouse; D016875:tau Proteins; D050995:Voltage-Dependent Anion Channel 1; D045647:DNA Glycosylases