Many people with Alzheimer’s disease start to suffer a loss of the brain’s white matter—a key regulator of cognition—long before their disease is diagnosed. What if this loss could be detected early and stopped?
That’s the goal of a research team led by the Case Western Reserve University School of Medicine. The researchers have identified a protein that, when overexpressed in the brain, causes the degeneration of white matter. And they’ve developed and patented a small-molecule drug that they believe could halt this process.
The protein is called Drp1, and, when there is too much of it in the brain, it injures oligodendrocytes, which are cells that produce protective the myelin sheaths around neurons. When they eliminated Drp1 expression in mouse models, it reduced tissue damage in the brain and improved cognition, they reported in the journal Science Advances.
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Drp1 is part of a three-pronged protein pathway that disrupts myelin-producing cells, the team found. The over-production of Drp1 causes an energy-related defect in oligodendrocytes. Eliminating the protein in mice corrected that errant process, they reported. They validated the findings using brain samples from deceased Alzheimer’s patients.
The new findings come at a critical time in Alzheimer’s research, as Biogen awaits an FDA verdict on aducanumab, a drug that has produced decidedly mixed results in clinical trials. Aducanumab is designed to target the beta amyloid plaques that are a hallmark of the disease. Earlier this month, an advisory committee to the FDA voted overwhelmingly against the prospect of the agency approving the drug, citing uncertainty about the clinical trial results. The FDA will hand down a verdict by March 7.
There are a handful of approved Alzheimer’s drugs, but they’re not designed to get at the root of the disease, said Andrew Pieper, Case Western professor and chair of neuropsychiatry, and a co-author of the new study, in a statement. “While these medicines augment neurotransmission to provide temporary symptomatic benefit, they do nothing to slow disease progression," he said.
Other research teams have focused on myelin’s role in Alzheimer’s. Last year, a team at Stanford University found that injecting a CD22 blocker into the brains of aged mice and found that it helped to clear myelin debris, which is another culprit in Alzheimer’s because it interferes with the brain’s ability to eliminate plaques and other detritus.
Over the summer, Roche made a big bet on an antibody that targets tau, another protein implicated in Alzheimer’s progression. It paid $120 million up front in a development deal with UCB, which is now running a proof-of-concept study in Alzheimer’s.
The Case Western team developed and patented a small molecule peptide inhibitor that regulates Drp1 expression. They hope to show that the drug can slow or reverse the progression of Alzheimer’s disease, they said.