DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice.

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Suberbielle E,Djukic B,Evans M,Kim DH,Taneja P,Wang X,Finucane M,Knox J,Ho K,Devidze N,Masliah E,Mucke L

doi

10.1038/ncomms9897

subject

Has Abstract

pub_date

2015-11-30 00:00:00

pages

8897

issn

2041-1723

pii

ncomms9897

journal_volume

6

pub_type

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