Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes.

Abstract

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimer's disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylenes (OPEs) exhibit selective binding and fluorescence turn-on in the presence of prefibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-β (Aβ) and α-synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of Aβ fibrils and compared its efficacy to the well-known but nonselective photosensitizer methylene blue (MB). Our results show that, while MB photo-oxidized both monomeric and fibrillar conformers of Aβ40, OPE oxidized only Aβ40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed but retained the characteristic β-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPE's photosensitizing activity overcomes the limitation of off-target oxidation of traditional photosensitizers and represents an advancement of PDT as a viable strategy to treat neurodegenerative disorders.

• Authors: Adeline M Fanni, Daniel Okoye, Florencia A Monge, Julia Hammond, Fahimeh Maghsoodi, Tye D Martin, Gabriella Brinkley, M Lisa Phipps, Deborah G Evans, Jennifer S Martinez, David G Whitten, Eva Y Chi
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 14 Issue 13 Pg. 14871-14886 (Apr 06 2022) ISSN: 1944-8252 [Electronic] United States
• PMID: 35344326 (Publication Type: Journal Article)

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Amyloidogenic Proteins
• Peptide Fragments

Topics

• Alzheimer Disease (metabolism)
• Amyloid (chemistry)
• Amyloid beta-Peptides (metabolism)
• Amyloidogenic Proteins
• Humans
• Peptide Fragments (chemistry)
• Protein Conformation, beta-Strand