Abstract
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.
Highlights
Maintaining DNA integrity is vital for all cells and organisms
breast cancer factor 1 (BRCA1) levels were decreased by 45% in human amyloid precursor protein (hAPP)-J20 mice (Supplementary Fig. 1a,b). hAPP-J20 mice had normal levels of BRCA1 mRNA in the dentate gyrus (DG) and parietal cortex (Fig. 1c and Supplementary Fig. 1c), suggesting post-transcriptional depletion of BRCA1 protein
Our study shows that BRCA1 critically contributes to double-strand breaks (DSBs) repair in central neurons and that neuronal reductions in BRCA1 cause increased persistence of DSBs, abnormal chromatin remodelling, cellular dysfunction and cognitive deficits
Summary
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. Human amyloid precursor protein (hAPP) transgenic mice from line J20, which simulate key aspects of AD5, had higher levels of neuronal DSBs at baseline and abnormal persistence of activity-induced neuronal DSBs4. In principle, these alterations could result from excessive formation or defective repair of DSBs. Because DNA repair is defective in several neurodegenerative diseases[1,2], we hypothesized that the abnormal accumulation of DSBs in neurons of hAPP mice is caused by alterations in their DNA repair machinery. Knocking down this factor in the dentate gyrus (DG) of mice increased neuronal DSB levels in this brain region and caused behavioural deficits without causing neuronal loss
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