Breast Cancer Gene BRCA1 Implicated In Alzheimer’s Disease

Researchers at the Gladstone Institutes in San Francisco – a nonprofit research group – have identified a link between the BRCA1 gene product and healthy memory and learning functions. The BRCA1 protein is found in lower than normal levels in the brains of people with Alzheimer’s disease, leading the researchers to postulate that a lack of the protein in neurons may lead to abnormal brain function and cognitive impairment indicative of the disease.

The BRCA1 gene was discovered in 1994 as an indicator of breast cancer risk in women with distinct mutations. The discovery sparked the invention of BRCA1 blood tests capable of detecting inherited mutations, which may mean a higher risk of developing ovarian and breast cancers.

The BRCA1 protein functions as a DNA repair mechanism that fixes breaks caused by damage to the DNA. When the BRCA1 gene is mutated, the resulting protein is unable to repair DNA damage, leading to a higher likelihood that the cells could accumulate further damage and eventually to the development of uncontrolled growth and cancer.

Previous research conducted by scientists at the Gladstone Institutes showed that neurons were potentially more vulnerable to DNA damage, which can occur under common circumstances including an increase in brain activity. Based on this result, the researchers developed the theory that the normal processes of DNA repair are an integral mechanism in proper learning and memory retention, and any disruption of these processes leads to an impairment in neuronal functioning.

In the current study, the researchers used genetically engineered mice with depleted levels of BRCA1 protein in their neuronal cells. The Gladstone Institutes investigators found that these mice accumulated DNA damage and displayed shrinkage of their neurons, which resulted in memory and learning deficits in the mice.

The symptoms displayed by the mice were similar to those observed in Alzheimer’s patients, leading the researchers to wonder about the BRCA1 protein levels in the brains of people with the neurodegenerative disease. The team then studied the post-mortem brains of patients with Alzheimer’s and found that levels of the BRCA1 protein were 65 to 75 percent lower than in non-Alzheimer’s control brains. The results of the research were published in the journal, Nature Communications.

Amyloid beta protein plaques in diseased brains have long been thought to be the cause of Alzheimer’s disease, however therapies designed to target the protein clumps have failed to be effective in treating the disease. Researchers are unsure whether the amyloid beta protein clumps are driving the cognitive symptoms of Alzheimer’s, or if they’re just a byproduct of the condition.

In order to test the potential link between amyloid beta and the BRCA1 protein depletion, the research team exposed healthy neurons cultured in the lab to amyloid beta proteins. The neurons were found to have lower levels of BRCA1 protein compared to untreated neurons, leading the researchers to suggest that the amyloid beta may be responsible for the BRCA1 depletion, and resulting cognitive decline.

The researchers plan to test whether increasing neuronal levels of BRCA1 protein can stop – or even reverse – neurodegeneration in Alzheimer’s patients. Despite the results of the study, the role of amyloid beta in Alzheimer’s progression remains a hotly-debated issue among researchers and drug developers.

Sources:

• Breast Cancer Gene BRCA1 May Play A Role In Alzheimer’s Disease – http://www.forbes.com/sites/emilymullin/2015/11/30/breast-cancer-gene-brca1-may-play-a-role-in-alzheimers-disease/
• Suberbielle, E., Djukic, B., Evans, M., Kim, D., Taneja, P., Wang, X., Finucane, M., Knox, J., Ho, K., Devidze, N., Masliah, E., and Mucke, L. (2015). DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nat Com, 6.