A study from researchers at the Gladstone Institutes in San Franciscohas examined the protein BRCA1, using a combination of tests onlaboratory mice and human brain tissue to determine that the proteinis central to learning and retaining memories. The work highlights theimportance of the protein in relation to the cognitive declineassociated with Alzheimer's disease, and could help in thedevelopment of future treatments.
Alzheimer'sis a degenerative condition affecting some 5.3 million people inthe US alone. We've seen numerous recent breakthroughs in the studyof the disease, including drugs that attack aspects of old age associated with the condition, and the identification of the mechanism that causes synapses in the brain to break down as it progresses.
Thenew research focuses on the protein BRCA1. In the past, BRCA1 hasbeen studied in dividing cells, where it plays a core role inrepairing a type of DNA damage, called a double-strand break, whereinboth strands of the double helix are severed.
Thingsare a little different in the brain, with double-strand breaksoccurring more regularly, and under normal conditions, such asfollowing a period of increased brain activity. The Gladstoneresearchers theorized that the cycle of DNA damage and repair in thebrain is actually what facilitates the learning process. Therefore,when decreased levels of BRCA1 are present, this function isdisrupted, leading to impaired cognitive function – a hallmark ofAlzheimer's disease.
Totest this theory, the scientists reduced BRCA1 levels in neurons inlaboratory mice. The results showed a build up of DNA damage, leadingto a decrease in learning and memory. With the findings tallying upwith the team's theory, it moved on to study the effect in specificrelation to Alzheimer's disease.
Todo so, the researchers analyzed neuronal BRCA1 levels in post-mortemAlzheimer's patient brains, comparing the findings with those takenfrom healthy tissue. They found that the levels of the protein werereduced by between 65 and 75 percent in the Alzheimer's patients'neurons – results that once again support the team's theory.
Havingestablished that BRCA1 plays a big role in the degenerativecondition, the researchers then approached the problem from a slightly different angle,recreating the process of the disease to determine what cause thedepletion of the protein. They introduced amyloid-beta proteins,which are central to Alzheimer's disease, building up to form harmfulplaques in the brain, to neurons grown in cell culture.
Asexpected, the amyloid-beta depleted the BRCA1 when introduced,strongly indicating that the protein, and its negative effects onBRCA1, are responsible for the faulty DNA repair witnessed inAlzheimer's patients' brains.
Lastly,the team used lab mice to demonstrate that increased amyloid-betacauses a decrease in BRCA1, but the next part of the study could wellbe the most exciting. Moving forward, the researchers will conduct tests on mice to see whether increasing BRCA1 levels can prevent, or evenreverse, the cognitive deficit caused by the condition.
"Therapeuticmanipulation of repair factors such as BRCA1 may ultimately be usedto prevent neuronal damage and cognitive decline in patients withAlzheimer's disease or in people at risk for the disease," says study lead author Lennart Mucke. "By normalizing the levels or functionof BRCA1, it may be possible to protect neurons from excessive DNAdamage and prevent the many detrimental processes it can set inmotion."
Thefindings of the study were published in the journal Nature.
Source:Gladstone Institutes
