Multifaceted Effects of a Multiple Nitric Oxide Photoreleaser and its Photoproducts on Amyloid‐β Aggregation

Aberrant aggregation of β-amyloid (Aβ) peptides into insoluble fibrils is recognized as one of the hallmarks of Alzheimer's disease (AD). Among the post-translational modifications influencing Aβ behavior, nitration and nitrosation by nitric oxide (NO) derivatives play a key role, though their impact on aggregation and toxicity remains unclear. This contribution explores the effects on Aβ aggregation induced by an NO photodonor (NOPD) releasing two NO molecules via a stepwise mechanism under the control of visible blue light. Significant reduction of protein aggregation is observed when a considerable amount NO (≈120 µM) is photoreleased during the early stages of the protein aggregation. In contrast, long-term release of a similar NO concentration is ineffective. On the other hand, proaggregative effect is induced by the NOPD kept in the dark. The stable photoproducts formed after the release of the first and the second molecule of NO also show a protein aggregation inhibitory effect both individually and in combination. Dynamic simulation studies are also reported to shed light on the binding of NOPD and its photoproducts with key Aβ_1-40 residues.