Key Insight for Alzheimer’s Drug Design: Fibrils Are Abundant in Soluble Amyloid Beta

In July 2023, lecanemab received full approval from the FDA for the treatment of early Alzheimer’s disease (AD). A phase 3 clinical trial published in NEJM demonstrated the drug can moderately slow AD-related cognitive decline.

The efficacy of lecanemab has been attributed to selectivity for free-floating bits of amyloid beta (Aβ) protein, called soluble protofibrils or soluble oligomers, rather than the fibrils that form Aβ plaques. Soluble Aβ forms are even more neurotoxic than Aβ fibrils: they disrupt neuron morphology, promote tau phosphorylation, accelerate Aβ seeding, and interfere with memory.

Researchers at Brigham and Women’s Hospital have redefined the nature of soluble Aβ, an advance pertinent to future drug design for AD. Andrew M. Stern, MD, PhD, an Assistant Professor and attending neurologist in the Department of Neurology, Dennis J. Selkoe, MD, the Vincent and Stella Coates Professor of Neurologic Diseases and co-director of the Ann Romney Center for Neurologic Diseases, and colleagues detail their findings in Neuron.

Short Fibrils Are Present in “Soluble” Aβ extracts

Soluble oligomers are so called because they aren’t pelleted when homogenates from the postmortem brain undergo ultracentrifugation. The research team previously developed an alternate method where instead of homogenizing tissue, they mince AD cerebral cortex into small bits to avoid shearing and breaking up plaques and other large Aβ aggregates, and soak the bits in physiological saline before ultracentrifugation.

They found that some of what researchers once thought were aqueously soluble forms of Aβ are actually very short, sedimentable fibrils:

  • Insoluble Aβ fibrils could be pelleted at high forces from the aqueous extracts of AD brain
  • Numerous short fibrils diffused into the extracts from 13 AD brain tissue samples, but only one control brain samples contained these
  • Under cryoelectron microscopy the structure of the diffusible Aβ fibrils matched the previously published structure of Aβ fibrils extracted from amyloid plaques

Target of Lecanemab Confirmed

The researchers found lecanemab readily binds to the small, diffusible Aβ fibrils. The drug also bound to intact amyloid plaques within slices from the same brain samples.

In several previous studies, Dr. Selkoe and colleagues showed that aqueous extracts of AD brain, but not control brain, can impair long-term potentiation (LTP) in wild-type mouse hippocampus. LTP is a rapid and persistent increase in synaptic transmission thought to be inhibited in AD. In this new study, as expected, adding lecanemab to AD mouse hippocampal slices prevented the inhibition of LTP.

The findings have exciting implications for a better understanding of AD pathogenesis and the development of additional Aβ-targeted disease-modifying therapies.

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