Carboranyl‐Curcuminoids for the Neutron Capture‐Based Treatment of Amyloid Aggregates in Alzheimer's Disease

ABSTRACT Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. The aggregation of amyloid‐beta (Aβ) peptides into oligomers and fibrils is central to its pathogenesis. While oligomers represent the most neurotoxic species, larger aggregates serve as reservoirs, maintaining pathological Aβ levels. To our knowledge, this study is the first to investigate Boron Neutron Capture Therapy (BNCT) as a method to selectively destabilize Aβ aggregates. This is achieved by inducing structural modifications in the Aβ peptide, aiming to convert fibrils into innocuous species. The approach utilizes ¹⁰ B‐enriched monocarbonyl analogs of curcumin (BMACs), a novel molecule that binds to Aβ fibrils and enables the site‐specific release of high‐linear‐energy‐transfer (LET) α particles and lithium ions upon neutron exposure. In vitro, Aβ aggregates were characterized using FESEM and Thioflavin T staining. The binding affinities of BMACs were determined through competition assays, with inhibition constants calculated using the Cheng‐Prusoff equation. Post‐irradiation analysis by ¹ H‐NMR and mass spectrometry demonstrated selective oxidation of histidine residues, a chemical modification capable of inducing fibril destabilization. This study provides proof of concept that not only offers future perspectives for Alzheimer's treatment but also enhances the understanding of radiation effects on proteins, particularly within the context of amyloidosis.