A fibril-selective single-domain antibody targets pathogenic amyloid-β assemblies and protects human neurons
Abstract
Alzheimer disease is characterized by extracellular amyloid-β deposition that contributes to neuronal dysfunction and degeneration. Although anti-amyloid-β antibodies reduce plaque burden, their use requires monitoring for amyloid-related imaging abnormalities. Here, phage display against immobilized Aβ40 fibrils representing a patient-relevant polymorph identified J8, a fibril-selective, Fc-free single-domain antibody. J8 bound fibrils with high apparent affinity, showed no detectable binding to monomeric Aβ40, decorated fibril surfaces, and recognized plaque-associated amyloid in Alzheimer disease brain tissue. During concurrent fibril exposure, J8 reduced apoptotic signaling in human induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids. Single-nucleus profiling of pooled organoids identified fibril-associated stress programs and opposite-direction expression patterns in the FibJ8 condition; fibril-associated changes showed the strongest directional concordance with advanced disease pathology. These findings identify J8 as a fibril-selective candidate and support organoid-based evaluation of anti-amyloid reagents as a fit-for-purpose preclinical tool.
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BibTeX
@article{greenlee2026fibrilselective,
title = {{A fibril-selective single-domain antibody targets pathogenic amyloid-β assemblies and protects human neurons}},
author = {Matt A. Greenlee and Soukaina Amniouel and Isabel Rivera and Jessica Suh and Natalia J. Martinez and Anton Simeonov and Elizabeth Head and Robert Tycko and Wei Zheng and Bryan D. Fleming and Qi Zhang},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117946},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03329-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A fibril-selective single-domain antibody targets pathogenic amyloid-β assemblies and protects human neurons
AU - Matt A. Greenlee
AU - Soukaina Amniouel
AU - Isabel Rivera
AU - Jessica Suh
AU - Natalia J. Martinez
AU - Anton Simeonov
AU - Elizabeth Head
AU - Robert Tycko
AU - Wei Zheng
AU - Bryan D. Fleming
AU - Qi Zhang
PY - 2026
DA - 2026/10/21
JO - iScience
DO - 10.1016/j.isci.2026.117946
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03329-8
AB - Alzheimer disease is characterized by extracellular amyloid-β deposition that contributes to neuronal dysfunction and degeneration. Although anti-amyloid-β antibodies reduce plaque burden, their use requires monitoring for amyloid-related imaging abnormalities. Here, phage display against immobilized Aβ40 fibrils representing a patient-relevant polymorph identified J8, a fibril-selective, Fc-free single-domain antibody. J8 bound fibrils with high apparent affinity, showed no detectable binding to monomeric Aβ40, decorated fibril surfaces, and recognized plaque-associated amyloid in Alzheimer disease brain tissue. During concurrent fibril exposure, J8 reduced apoptotic signaling in human induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids. Single-nucleus profiling of pooled organoids identified fibril-associated stress programs and opposite-direction expression patterns in the FibJ8 condition; fibril-associated changes showed the strongest directional concordance with advanced disease pathology. These findings identify J8 as a fibril-selective candidate and support organoid-based evaluation of anti-amyloid reagents as a fit-for-purpose preclinical tool.
SN - 2589-0042
ER -