title: 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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Suberbielle
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors.forename: Biljana
authors.initials: B
authors.lastname: Djukic
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Evans
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Taneja
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
authors.forename: Mariel
authors.initials: M
authors.lastname: Finucane
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Knox
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.affiliation: Department of Neuroscience, University of California, San Diego, La Jolla, California 92093, USA.|Department of Pathology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D003071:Cognition; D004260:DNA Repair; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019313:BRCA1 Protein