Summary: Researchers have unveiled the structure of a unique amyloid beta protein associated with Alzheimer’s progression. This protein forms small aggregates that disrupt brain function.
Importantly, the study found that lecanemab, a recently FDA-approved Alzheimer’s treatment, can neutralize these disruptive aggregates, hinting at its potential to slow down the disease’s cognitive decline.
Key Facts:
- Researchers have detailed the structure of a distinct type of amyloid beta plaque protein that plays a role in Alzheimer’s disease progression. These proteins form small, diffusible aggregates that can disrupt neuronal function across various regions of the brain.
- Lecanemab, an antibody therapy recently approved by the FDA for Alzheimer’s treatment, has been found to neutralize these small, diffusible amyloid beta protein aggregates. This suggests it may play a significant role in slowing cognitive decline in patients with early Alzheimer’s disease.
- The study also provided a clearer definition of the ‘protofibril’ or ‘oligomer’ structures that lecanemab binds to, potentially offering valuable insights into the drug’s mechanism of action against Alzheimer’s disease.
Source: Cell Press
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 May 10 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.
As a cause of dementia, AD affects more than 50 million people worldwide. 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.
Currently, there is no cure for the disease. But in recent years, scientists have developed new treatments that can reduce AD symptoms such as memory loss.
“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 U.S. Food and Drug Administration 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, which are tiny, freely floating clumps of the amyloid beta protein.
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, a neurologist at the Brigham and Women’s Hospital.
“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?”
Stern, Selkoe, and their team successfully isolated the free-floating amyloid beta aggregates by soaking postmortem brain tissues from typical AD patients in saline solutions, which were then spun at high speed.
These tiny aggregates of amyloid beta protein access important brain structures such as the hippocampus, which plays a major role in memory.
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.
“If you don’t know your enemies, it’s hard to defeat them,” Selkoe says.
“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.”
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.
Funding: This work is supported by the National Institutes of Health, the Alzheimer’s Association, the Davis Alzheimer’s Prevention Program at BWH, and the UK Medical Research Council.
About this neuropharmacology and Alzheimer’s disease research news
Author: Kristopher Benke
Source: Cell Press
Contact: Kristopher Benke – Cell Press
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer’s disease brains” by Dennis Selkoe et al. Neuron
Abstract
Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer’s disease brains
Highlights
- Aβ in aqueous brain extracts (oligomers, protofibrils) are insoluble and fibrillar
- The diffusible Aβ fibrils have the same atomic structure as amyloid plaque fibrils
- Lecanemab binds to and protects against the synaptotoxicity of diffusible fibrils
Summary
Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer’s disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures.
We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer.
The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes.
Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques.
These findings have implications for AD pathogenesis and drug design.
