Catalytic-Defect Passivation on Amyloid-β Fibrils Using Atomically Precise Gold Nanoclusters
Year: 2026
Type: preprint
Abstract: Most pharmacological strategies targeting amyloid-β (Aβ) in Alzheimer’s disease have focused on reducing Aβ production, preventing aggregation, or removing deposited amyloid from the brain. Within the Aβ aggregation pathway, secondary nucleation is a critical amplification step in which pre-existing fibrils catalyze the formation of new aggregates on their surfaces. Some of these aggregates detach and grow into additional fibrils, sustaining an autocatalytic cycle that makes secondary nucleation an attractive target for pharmacological intervention. Biophysical studies indicate that rare defects formed during fibril growth act as hotspots for secondary nucleation, and that fibrils with fewer such defects show markedly lower secondarynucleation activity. Therefore, these findings raise the possibility that defect passivation could reduce the catalytic activity of Aβ fibrils without requiring their removal. This topical review proposes atomically precise, ligand-protected gold nanoclusters (AuNCs) as a tunable platform for selectively targeting and blocking these catalytic defects. Taking advantage of their welldefined metal cores and customizable ligand layers, we outline how AuNCs can be engineered for selective recognition of fibril surfaces and catalytic inhibition. We introduce an inversedesign strategy that integrates molecular modeling with machine learning-guided screening to identify optimal AuNC candidates before validating them through aggregation kinetics and neuronal assays. Defect-selective passivation would offer a distinct anti-amyloid approach by suppressing the critical autocatalytic amplification step of Aβ aggregation rather than removing deposited amyloid.
Source: ChemRxiv
Authors: Bruno A. Cisterna, María Francisca Matus
Institutions: Augusta University, University of Jyväskylä
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214579589