Low levels of BRCA1 in the brain may contribute to dementia

Researchers have found that the breast cancer BRCA1 protein plays a key role in repairing DNA in the brain. They also learned that amyloid beta reduces BRCA1 in patients with dementia, leading to cognitive deficits of learning and memory, according to a study published online November 30, 2015 in the journal Nature Communications.

“It’s extremely interesting that one molecule can be critically involved in two apparently opposing conditions: cancer, in which too many cells are born, and neurodegenerative disease, in which too many brain cells die off,” said senior author Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and the Joseph B. Martin Distinguished Professor of Neuroscience at the University of California San Francisco, CA.

In this investigation, Dr. Mucke and colleagues sought to understand how defective repair of DNA in the brain contributes to neurological disorders, including Alzheimer’s disease. They first performed postmortem examinations of brains in patients with Alzheimer’s disease and compared them with brains of people without Alzheimer’s. They discovered that the Alzheimer’s patients had low levels of BRCA1. The researchers also found reductions of BRCA1 in the brains of mouse models of Alzheimer’s, which led them to conclude that BRCA1 plays a key role in DNA repair in the brain.

The researchers then experimentally tested these findings by reducing BRCA1 levels in the brains of healthy mice, which made their brain cells shrink and become dysfunctional. The mice also developed problems with learning and memory. Reducing BRCA1 also caused increased DNA damage in the brains of Alzheimer’s mice.

Finally, the researchers performed an in vitro experiment in which they added amyloid beta to neurons, which lowered levels of BRCA1. This finding suggested that accumulation of amyloid beta lowers levels of BRCA1, which increases DNA damage in brain cells and may contribute to dementia, Dr. Mucke said.

“An emerging theme in neurodegeneration research is that normal DNA repair protects against damage that causes neurons to die in dementia and related disorders,” said Roderick Corriveau, PhD, Program Director at the National Institute of Neurological Disorders and Stroke, which helped fund the research. “This study supports and strengthens that theme by showing that beta-amyloid decreases the levels of the DNA repair gene BRCA1, and at the same time inhibits the ability to form new memories.”

The question remains whether mutations in BRCA1 that increase the risk for breast and other cancers also change the DNA repair function of BRCA1 in the brain, the authors noted.

“The functions of BRCA1 in the brain remain to be fully elucidated, but our findings suggest that it may play an important role in supporting critical brain functions in both health and disease,” Dr. Mucke said. The researchers called for further studies to determine whether BRCA1 could be a potential therapeutic target for treating dementia.