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Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices
Published on: July 14, 2010
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Relationship between efficacy and preferential targeting of soluble Aβ aggregates
Johanne M Kaplan1, Ebrima Gibbs2, Juliane A Coutts2
1ProMIS Neurosciences One Broadway Cambridge Massachusetts USA.
Alzheimer'S & Dementia (New York, N. Y.)
|December 1, 2025
Summary
Antibodies targeting toxic amyloid beta (Aβ) oligomers, not monomers, show promise for Alzheimer's disease (AD) treatment. This selectivity may improve efficacy and reduce side effects like ARIA.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Alzheimer's disease (AD) treatments targeting amyloid beta (Aβ) have shown variable efficacy.
- Understanding the binding specificities of Aβ-directed antibodies is crucial for therapeutic development.
Purpose of the Study:
- To investigate the relationship between the molecular species targeted by Aβ-directed antibodies and their therapeutic efficacy and safety.
- To assess how monomer competition affects antibody binding to toxic Aβ oligomers.
Main Methods:
- Surface plasmon resonance used to quantify antibody binding to Aβ monomers and oligomers from AD brains.
- Immunohistochemistry and immunofluorescence assessed antibody binding to plaques.
- In vivo testing of antibody PMN310 in AD mouse models.
Main Results:
- Clinical antibodies (lecanemab, aducanumab, donanemab) and investigational antibodies (PMN310, ACU193) demonstrated selectivity for oligomers over monomers.
- PMN310 showed no plaque binding and protected cognition in mouse models without causing microhemorrhages.
- Previously failed antibodies lost oligomer binding in the presence of monomers.
Conclusions:
- Selectivity for toxic soluble Aβ oligomers correlates with improved clinical efficacy in Alzheimer's disease.
- Avoiding Aβ monomers enhances binding to pathogenic oligomers.
- Reduced binding to plaques and vascular deposits may mitigate amyloid-related imaging abnormalities (ARIA).
