A team of researchers at Gladstone Institutes has identified a possible contributing factor for the cognitive degeneration in Alzheimer’s disease (AD), suggesting that part of the problem may reside in the lack of certain molecules involved in the reparation of damaged DNA. While further work is needed in order to convert this information into new therapies, the research opens up the possibility of protecting neurons from becoming damaged by manipulating levels of these proteins.
Publishing their findings in Nature Communications, the team explained that, under normal conditions, increases in brain activity generate temporary double strand breaks (DSBs) in neuronal DNA, which are then quickly repaired by a number of proteins. A key gene involved in the expression of these proteins is BRCA1. However, when this DNA repair mechanism is deficient, the DSBs are not fixed, resulting in permanent neuronal damage and impairing a number of vital cognitive functions such as learning and memory.
By examining the brains of deceased AD sufferers, the team noted that BRCA1 levels were 65 to 75 percent lower than in brains of non-sufferers, suggesting that a lack of these repair proteins could well play a major role in the condition. To add weight to this hypothesis, the researchers conducted a series of tests on mice that had been genetically modified to carry a human protein called the amyloid precursor protein. This is known to have a central role in the development of AD, and when expressed in mice certain aspects of AD are simulated.
Levels of BRCA1 were found to be up to 70 percent lower than normal in these mice, resulting in a significant increase in DSBs – particularly in a brain region known as the dentate gyrus (DG). This, in turn, caused neurons to shrink, their connections to be impaired, and learning and memory deficits.
Similar effects were observed when the researchers exposed neuronal cell cultures with amyloid-beta proteins, pointing to the strong possibility that the accumulation of certain amyloid proteins causes a depletion of neuronal BRCA1, thereby inhibiting key DNA repair mechanisms in the brain.
This information supplements other recent studies that have identified alternative pathways by which amyloid proteins cause AD. For instance, a paper which appeared in the same journal last week indicated that amyloid-beta proteins break down another brain protein called neural cell adhesion molecule 2 (NCAM2), which physically connects synaptic membranes. In doing so, it ensures the stability of the gaps between neurons, across which neurotransmitters pass in order to transport signals. However, the scientists behind the study found that AD sufferers experienced a loss of synapses, thereby reinforcing the connection between the presence of amyloid-beta proteins and the disease.
Regarding the BRCA1 study, co-author Lennart Mucke explained in a statement that this information could soon be used to create novel treatments for AD. “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,” he said.