FDA-Approved Alzheimer’s Drug Could Help Preventing More Damage to the Brain

For the first time, researchers described the structure of a special type of amyloid beta plaque protein associated with Alzheimer’s disease (AD) progression. In a report published in the journal Neuron, scientists showed the small aggregates of the amyloid beta protein could float through the brain tissue fluid, reaching many brain regions and disrupting local neuron functioning. The research also provided evidence that a newly approved AD treatment could neutralize these small, diffusible aggregates.

Previous research has discovered that AD patients have abnormal build-up of a naturally occurring substance “amyloid beta protein” in the brain that can disrupt neurotransmission. 

“The paper is timely because, for the first time in human history, we have an agent that can actually treat people with Alzheimer’s in a way that could slow their cognitive decline,” says Dennis Selkoe, the paper’s corresponding author at the Brigham and Women’s Hospital in Boston. “And we’ve never been able to say those words until the last few months.”

In January, the FDA approved lecanemab, an antibody therapy for treating AD. In a phase III clinical trial, lecanemab slowed cognitive decline in patients with early AD. Scientists suspect the drug’s positive effect may be associated with its ability to bind and neutralize soluble amyloid beta protein aggregates, also known as protofibrils or oligomers. These small clumps can form in the brain before aggregating further into large amyloid plaques. The small aggregates can also break off and diffuse away from amyloid plaques that are already there.

“But nobody’s really been able to define with any structural rigor what is a ‘protofibril’ or ‘oligomer’ that lecanemab binds to,” says first author Andrew Stern. “Our work identifies that structure after isolating it from the human brain.”

Working with colleagues at the Laboratory for Molecular Biology in Cambridge, UK, they determined the atomic structure of these tiny aggregates, down to the individual atom.

Next, the team plans to observe how these tiny amyloid beta aggregates travel through living animal brains and study how the immune system responds to these toxic substances. Recent research has shown that the brain’s immune system reaction to amyloid beta is a key component of AD.

“If we can figure out exactly how these tiny, diffusible fibrils exert toxicity, then maybe the next AD drugs can be better,” Stern says.

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Sources:

Andrew M. Stern, Yang Yang, Shanxue Jin, Keitaro Yamashita, Angela L. Meunier, Wen Liu, Yuqi Cai, Maria Ericsson, Lei Liu, Michel Goedert, Sjors H.W. Scheres, Dennis J. Selkoe. Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer’s disease brains. Neuron, 2023; DOI: 10.1016/j.neuron.2023.04.007

Cell Press. “FDA-approved Alzheimer’s drug lecanemab could prevent free-floating amyloid beta fibrils from damaging the brain.” ScienceDaily. ScienceDaily, 10 May 2023. <www.sciencedaily.com/releases/2023/05/230510120523.htm>.

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