Low levels of the BRCA1 protein in brain cells may be associated with dementia caused by Alzheimer’s disease, according to new evidence from the brains of deceased patients with Alzheimer’s disease or mild cognitive impairment, as well as experimental mouse models of the disease.
Elsa Suberbielle, D.V.M., Ph.D., of Gladstone Institute of Neurological Disease, San Francisco, and her colleagues found low levels of BRCA1 protein, a DNA repair enzyme, in the brains of deceased Alzheimer’s and mild cognitive impairment patients, compared with controls, as well as in mouse models of Alzheimer’s. Mutations in BRCA1 are associated with ovarian and breast cancers.
Further experiments in wild-type mice showed that experimental lowering of BRCA1 levels in the dentate gyrus caused neuronal dysfunction and shrinkage, as well as impairments in synaptic plasticity, excessive neuronal excitability, spatial learning and memory deficits, and increased DNA damage. The addition of beta-amyloid oligomers to cultures of neurons also lowered BRCA1 protein levels in the cells. Low levels of BRCA1 did not appear to cause these deficits through increased neuronal apoptosis or loss.
Additional research will be necessary to determine whether BRCA1 mutations that lead to cancer also affect brain function and whether the neuronal dysfunction caused by low BRCA1 levels results from faulty repair of double-stranded DNA breaks or from reductions in other functions performed by BRCA1, the investigators said.
The full paper is published in Nature Communications (2015 Nov 30. doi: 10.1038/ncomms9897).