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Depletion of Normal BRCA1 Protein in Neurons Linked to Alzheimer’s Disease; Non-Mutated BRCA1 Required for Normal Learning & Memory; First-Ever Such Results Reported by Gladstone Institutes

Researchers from the Gladstone Institutes in San Francisco have shown, for the first time, that the unmutated BRCA1 (breast cancer 1) protein is required for normal learning and memory and is depleted by Alzheimer’s disease. BRCA1 is a key protein involved in DNA repair, and mutations that impair its function increase the risk for breast and ovarian cancer. The new study, published online today (November 30, 2015) in an open-access article in Nature Communications, demonstrates that Alzheimer’s disease is associated with a depletion of BRCA1 protein in neurons and that BRCA1 depletion can cause cognitive deficits. The article is titled ““DNA Repair Factor BRCA1 Depletion Occurs in Alzheimer Brains and Impairs Cognitive Function in Mice.” “BRCA1 has so far been studied primarily in dividing (multiplying) cells and in cancer, which is characterized by abnormal increases in cell numbers,” says first author Elsa Suberbielle, Ph.D., a research scientist at the Gladstone Institutes. “We were therefore surprised to find that it also plays important roles in neurons, which don’t divide, and in a neurodegenerative disorder [Alzheimer’s disease] that is characterized by a loss of these brain cells.” In dividing cells, BRCA1 helps repair a type of DNA damage known as double-strand breaks that can occur when cells are injured. In neurons, though, such breaks can occur even under normal circumstances in the absence of cell division, for example, after increased brain activity, as shown by the team of Gladstone scientists in an earlier study. The researchers speculated that, in brain cells, cycles of DNA damage and repair facilitate learning and memory, whereas an imbalance between damage and repair disrupts these functions. To test this idea, the scientists experimentally reduced BRCA1 levels in the neurons of mice. Reduction of the DNA repair factor led to an accumulation of DNA damage and to neuronal shrinkage. This reduction of BRCA1 protein also caused learning and memory deficits. Because Alzheimer’s disease is associated with similar neuronal and cognitive problems, the scientists wondered whether the problems might be mediated by depletion of BRCA1. They therefore analyzed neuronal BRCA1 levels in post-mortem brains of Alzheimer’s patients. Compared with non-demented controls, neuronal BRCA1 levels in the patients were found to be reduced by 65-75%. To determine the causes of this depletion, the investigators treated neurons grown in cell culture with amyloid-beta proteins, which accumulate in Alzheimer brains. These proteins depleted BRCA1 in the cultured neurons, suggesting that they may be an important cause of the faulty DNA repair seen in Alzheimer brains. Further supporting this conclusion, the researchers demonstrated that accumulation of amyloid-beta in the brains of mice also reduced neuronal BRCA1 levels. They are now testing whether increasing BRCA1 levels in these mouse models can prevent or reverse neurodegeneration and memory problems.

“Therapeutic manipulation of repair factors such as BRCA1 may ultimately be used to prevent neuronal damage and cognitive decline in patients with Alzheimer’s disease or in people at risk for the disease,” says senior author Lennart Mucke, M.D., Director of the Gladstone Institute of Neurological Disease. “By normalizing the levels or function of BRCA1, it may be possible to protect neurons from excessive DNA damage and prevent the many detrimental processes it can set in motion.”

Other Gladstone investigators on the study include Biljana Djukic, Mark Evans, Daniel Kim, Praveen Taneja, Xin Wang, Mariel Finucane, Joseph Knox, Kaitlyn Ho, and Nino Devidze. Eliezer Masliah from the University of California, San Diego also took part in the research.

This report is based on a Gladstone Institutes news release written by Gladstone’s Dana Smith, Ph.D., and on a related report in Neuroscience News.

This image shows reduced levels of BRCA1 (red) in neurons (blue). Amyloid-beta plaques in the brain can deplete neurons of BRCA1, potentially contributing to cognitive deficits in Alzheimer’s disease. (Credit: Elsa Suberbielle).

[Press release] [Neuroscience News article] [Nature Communications article]