Researchers have revealed the structure of an amyloid beta protein implicated in the progression of Alzheimer’s disease and provided a window into how the recently approved drug lecanemab works.
The team found abundant small diffusible aggregates of amyloid beta protein in aqueous extracts from the brains of people with Alzheimer’s who had died.
These insoluble fibrils had identical structures to the fibrils found in the amyloid plaques that collect between neurons, disrupt cell function, and are a hallmark of Alzheimer’s disease.
The insoluble fibrils inhibited synaptic transmission and were bound and blocked by the new Alzheimer’s drug lecanemab, the researchers report in the journal Neuron.
The team believes that lecanemab’s therapeutic target therefore includes diffusible fibrils with the same structures as those from plaques.
“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,” said corresponding author Dennis Selkoe, PhD, co-director at the center for neurologic diseases at Brigham and Women’s Hospital in Boston.
“If you don’t know your enemies, it’s hard to defeat them,” he added. “It was a very nice coincidence that all this work we were doing came right alongside the time that lecanemab became widely known and available.
“This research brings together the identity of the bad guy and something that can neutralize the bad guy.”
Lecanemab is a monoclonal antibody that was approved in the U.S for the treatment of early Alzheimer’s disease in January this year.
Its success has been attributed to selectivity for soluble amyloid beta protofibrils over insoluble fibrils. However, a structural definition of protofibrils or oligomers—which the researchers collectively term aggregates—in human brains does not exist.
Maintaining that improving Alzheimer’s therapy requires a structural understanding of aqueous amyloid beta aggregates, the team studied extracts from the brains of people who had died with Alzheimer’s disease.
They unexpectedly discovered amyloid beta fibrils in synaptotoxic high-speed supernatants from these brains that were extracted by soaking in an aqueous buffer.
The amyloid beta aggregates in aqueous brain extracts—oligomers and protofibrils—were insoluble and fibrillar and had the same atomic structure as amyloid plaque fibrils.
Lecanemab bound to and protected against the synaptotoxicity of diffusible fibrils.
Lead investigator Andrew Stern, PhD, a neurologist also at the Brigham and Women’s, said that no one had previously been able to define with any structural rigor what the protofibril or oligomer was that lecanemab bound to.
“Our work identifies that structure after isolating it from the human brain. That’s important because patients and drug developers will want to know what exactly lecanemab binds to. Could that reveal something special about how it works?”
