17 May 2023

In their quest to study the elusive, toxic Aβ fibrils suspended in the interstitial fluid within Alzheimer’s disease brains, a collaboration of scientists has finally nailed down the fibrils' structure after isolating them following ultracentrifugation. “What we thought were purely soluble aggregates of Aβ, i.e. ‘soluble oligomers,’ are actually tiny particulate fibrils of Aβ that have the same atomic structure as the insoluble fibrils that comprise amyloid plaques,” said Dennis Selkoe at Brigham and Women’s Hospital, Boston.

Lecanemab, the FDA-approved anti-amyloid antibody originally developed by Lars Lannfelt at Sweden's Uppsala University to bind to such tiny Aβ fibrils—Lannfelt called them protofibrils—bound these particulates Selkoe's group has now isolated from human AD brain. Alzforum covered this work when a preprint was uploaded to bioRXiv (Nov 2022 news).

In the May 10 Neuron, Selkoe and colleagues expand on that manuscript, reporting that these easily isolated fibrils are toxic to neurons. First author Andrew Stern had proposed that, in the brain, these fibrils congregate around dense-core plaques, occasionally meandering into nearby synaptic clefts to cause trouble. He now reports that they impair long-term potentiation in brain slices from wild-type mice. Adding lecanemab to the slices normalized LTP, likely preventing synaptotoxicity by soaking up the fibrils (see image below).

Lecanemab Restores LTP. In mouse hippocampal slices, Aβ fibrils from aqueous AD extracts (orange, left) impaired long-term potentiation. Lecanemab preserves plasticity (blue, right). [Courtesy of Stern et al., Neuron, 2023.]

Selkoe told Alzforum his team is now extracting soluble Aβ fibrils from meningeal vessels and parenchymal plaque deposits from AD tissue. The goal is to compare the toxicity of each and see how well different anti-amyloid antibodies bind to them. “These experiments are aimed at learning more about differential effects of the Aβ-clearing antibodies in inducing vascular side effects, such as ARIA-E,” Selkoe told Alzforum. ARIA can occur when antibodies bind to Aβ fibrils in blood vessels.—Chelsea Weidman Burke

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References

News Citations

1. Short Aβ Fibrils Easily Isolated from Alzheimer's Brain Fluid 10 Nov 2022

Further Reading

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