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

Author

Listed:
  • Elsa Suberbielle

    (Gladstone Institute of Neurological Disease
    University of California, San Francisco)

  • Biljana Djukic

    (Gladstone Institute of Neurological Disease)

  • Mark Evans

    (Gladstone Institute of Neurological Disease
    University of California, San Francisco)

  • 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
    Present address: Bristol-Myers-Squibb, 5 Research Parkway, Wallingford Center, Connecticut 06492, USA.)

  • Eliezer Masliah

    (University of California, San Diego
    University of California, San Diego)

  • Lennart Mucke

    (Gladstone Institute of Neurological Disease
    University of California, San Francisco)

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.

Suggested Citation

  • Elsa Suberbielle & Biljana Djukic & Mark Evans & Daniel H. Kim & Praveen Taneja & Xin Wang & Mariel Finucane & Joseph Knox & Kaitlyn Ho & Nino Devidze & Eliezer Masliah & Lennart Mucke, 2015. "DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9897
    DOI: 10.1038/ncomms9897
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    Cited by:

    1. Thomas Bourquard & Kwanghyuk Lee & Ismael Al-Ramahi & Minh Pham & Dillon Shapiro & Yashwanth Lagisetty & Shirin Soleimani & Samantha Mota & Kevin Wilhelm & Maryam Samieinasab & Young Won Kim & Eunna H, 2023. "Functional variants identify sex-specific genes and pathways in Alzheimer’s Disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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