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

Elsa Suberbielle (), Biljana Djukic, Mark Evans, Daniel H. Kim, Praveen Taneja, Xin Wang, Mariel Finucane, Joseph Knox, Kaitlyn Ho, Nino Devidze, Eliezer Masliah and Lennart Mucke ()
Additional contact information
Elsa Suberbielle: Gladstone Institute of Neurological Disease
Biljana Djukic: Gladstone Institute of Neurological Disease
Mark Evans: Gladstone Institute of Neurological Disease
Daniel H. Kim: Gladstone Institute of Neurological Disease
Praveen Taneja: Gladstone Institute of Neurological Disease
Xin Wang: Gladstone Institute of Neurological Disease
Mariel Finucane: Gladstone Institute of Cardiovascular Disease
Joseph Knox: Gladstone Institute of Neurological Disease
Kaitlyn Ho: Gladstone Institute of Neurological Disease
Nino Devidze: Gladstone Institute of Neurological Disease
Eliezer Masliah: University of California, San Diego
Lennart Mucke: Gladstone Institute of Neurological Disease

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms9897 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9897

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms9897

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().