Photodynamic suppression of $\beta$-amyloid peptide self-assembly

Abstract

The abnormal aggregation of beta-amyloid ($A\beta$) peptides is the representative pathological hallmark of Alzheimer’s disease (AD). For several decades, the causative role of Aβ aggregation in AD pathology has been widely supported by the numerous in vivo and in vitro data. Therefore, tremendous amounts of efforts have been made to explore therapeutic agents that can modulate the aggregation of $A\beta$. Nevertheless, none of the efforts succeeded to release commercially available drugs, leading to needs for the novel approach. In this thesis, the regulation of $A\beta$ amyloidogenesis by light‐induced photosensitizing molecules is addressed.

Chapter 1 provides an overview of the recent attempts that employ light energy to intervene the self-assembly of $A\beta$ peptides via the generation of oxidative stress by photosensitizers, such as natural or synthetic dyes, light-responsive nanomaterials, and photoelectrochemical platforms.

Chapter 2 and 3 describe a light-induced suppression of $A\beta$ aggregation in vitro and $A\beta$ neurotoxicity in vivo by porphyrin molecules and methylene blue (MB), respectively. Multiple photochemical analyses verified that photo-activated meso‐tetra(4‐sulfonatophenyl)porphyrin (TPPS) and MB successfully inhibits $A\beta$ aggregation in vitro. Furthermore, the photosensitizing molecules suppressed neural cell death, synaptic toxicity, and behavioral defects in the Drosophila AD model and rescued larval locomotion defect and short lifespan caused by $A\beta$ overexpression under LED light illumination. Finally, disaggregation capability of photoexcited MB against the pre-existing $A\beta_{42}$ aggregates is demonstrated.

Chapter 4 presents the in-depth studies to monitor the effect of photosensitized Thioflavin-T (ThT) on $A\beta_{42}$ aggregation. The structural changes in amino acid residues of $A\beta_{42}$ by photoexcited ThT was monitored using solution NMR and mass spectrometry. The chemical kinetics analysis was utilized to observe the aggregation behaviour of the oxidized $A\beta_{42}$. The underlying mechanism of photodynamic suppression of $A\beta$ aggregation and the dilemma in generating oxidative stress in vivo are also discussed.