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DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice
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DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice
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Journal Article
DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice
2015
Overview
Maintaining DNA integrity is vital for all cells and organisms. Defective DNA repair may contribute to neurological disorders, including Alzheimer’s disease (AD). We found reduced levels of BRCA1, but not of other DNA repair factors, in the brains of AD patients and human amyloid precursor protein (hAPP) transgenic mice. Amyloid-β oligomers reduced BRCA1 levels in primary neuronal cultures. In wild-type mice, knocking down neuronal BRCA1 in the dentate gyrus caused increased DNA double-strand breaks, neuronal shrinkage, synaptic plasticity impairments, and learning and memory deficits, but not apoptosis. Low levels of hAPP/Amyloid-β overexpression exacerbated these effects. Physiological neuronal activation increased BRCA1 levels, whereas stimulating predominantly extrasynaptic
N
-methyl-
D
-aspartate receptors promoted the proteasomal degradation of BRCA1. We conclude that BRCA1 is regulated by neuronal activity, protects the neuronal genome, and critically supports neuronal integrity and cognitive functions. Pathological accumulation of Aβ depletes neuronal BRCA1, which may contribute to cognitive deficits in AD.
DNA repair deficits have been suggested to play a role in Alzheimer’s pathology. Here, the authors report reduced levels of the DNA repair factor BRCA1 in patient brains, and provide evidence that loss of BRCA1 in the dentate gyrus leads to spatial learning and memory deficits in mice.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
Subject
/ 13/51
/ 14/63
/ 38/44
/ 38/89
/ 64/60
/ 82/1
/ 9/30
/ 96/106
/ Aged
/ Alzheimer Disease - genetics
/ Alzheimer Disease - metabolism
/ Alzheimer Disease - physiopathology
/ Alzheimer Disease - psychology
/ Amyloid beta-Peptides - genetics
/ Amyloid beta-Peptides - metabolism
/ Animals
/ DNA
/ Female
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Male
/ Mice
/ N-Methyl-D-aspartic acid receptors
/ Proteins
/ Psychiatrics and mental health
/ Repair
/ Rodents
/ Science
