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BRCA1 Also Linked to Alzheimer’s Disease

BRCA1

The protein BRCA1 has been found to be also required for normal learning and memory and is depleted by Alzheimer's disease, according to a study by researchers from the Gladstone Institutes.

The basic function of the protein BRCA1 is DNA repair, and mutations in the gene for this protein increase
the risk of acquiring breast and ovarian cancer. The study by the Gladstone Institutes was published in
Nature Communications, and it showed that Alzheimer's disease can cause a deficit of BRCA1 in neurons,
which in turn can cause cognitive defects.

Elsa Suberbielle, PhD, the first author of the study and a research scientist at the Gladstone Institutes says
that BRCA1 has so far been studied primarily in dividing cells and in cancer, which is characterized by
abnormal increases in cell numbers. This is the reason why they were surprised that the protein also
plays an important role in neurons, which don't divide once mature, and pretty much more in a
neurodegenerative disease that involves a loss of these cells.

In normally dividing cells, BRCA1 is involved in a specific type of DNA damage which are called double-
strand breaks, and this type of damage happens when cells are injured. In the case of neurons, however,
double-strand breaks can happen even in normal circumstances. In a previous study, the scientists were
able to show that these breaks can happen after increased brain activity. Based on these results, they
hypothesized that a cycle of DNA damage and repair actually normally occurs in neurons, and these cycles
are the ones assist in learning and memory. Hence, an imbalance between the two processes of damage
and repair would thereby cause learning and memory deficits.

BRCA1

In order to confirm this hypothesis, the researchers experimentally caused a depletion in the BRCA1
protein level of mice neurons. BRCA1 reduction caused an accumulation of DNA damage and also caused
the neurons to shrink, consequently also causing memory and learning deficits. As Alzheimer's disease is
also characterized by such deficits, the researchers tried to check if these deficits were also mediated by
BRCA1.

Analyzing BRCA1 levels in the post-mortem brains of Alzheimer's patients, they found out that neuronal
BRCA1 levels were reduced by 65-75% when compared with non-demented controls. In Alzheimer's
disease, a protein known as amyloid-beta accumulates, and the scientists tried treating neuron cell
cultures with it. The treatment of amyloid-beta to neuronal cells resulted in a depletion of BRCA1, which
suggests that BRCA1 may indeed be involved in the malfunctioning DNA repair system seen in the brains
of patients with Alzheimer's. In order to further support this claim, the scientists also induced a buildup
of amyloid-beta in the brains of mice, which also reduced neuronal BRCA1 levels. Currently, they are trying
to check whether an increase in the levels of BRCA1 would be able to prevent or reduce
neurodegeneration as well as the subsequent adverse effects on cognition and memory. Lennart Mucke,
MD, senior author and director of the Gladstone Institute of Neurological Disease, says that 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.