Research Projects

Alzheimer’s disease (AD) is a progressive and currently incurable neurodegenerative disorder, clinically manifested by cognitive decline, memory loss, and behavioral deterioration.¹ One of the key pathological hallmarks of AD is the formation of amyloid fibrils—highly stable, insoluble protein aggregates primarily composed of amyloid-β (Aβ) peptides.² These fibrils possess a characteristic cross-β-sheet structure, and their formation is profoundly influenced by the surrounding microenvironment, particularly local pH. Acidic conditions facilitate fibrillogenesis by protonating basic residues, thereby reducing intermolecular repulsion and promoting aggregation. In contrast, basic pH destabilizes fibrils and can lead to disassembly of preformed aggregates. While most existing phototherapeutic strategies focus on early-stage inhibition of amyloid aggregation, effective intervention at later stages—especially defibrillogenesis—remains largely unaddressed. Our recent work has shown that a photoresponsive cage can sense and inhibit Aβ aggregation via controlled photorelease of valproic acid.³ However, this system lacks the ability to disintegrate matured fibrils or dynamically modulate the pH microenvironment in a controlled manner. This proposal aims to fill this critical gap by developing a wavelength-selective, light-triggered platform for dynamic pH modulation using photoacids and photobases (Scheme 1A). These molecules can undergo dramatic changes in acidity or basicity upon light irradiation, enabling non-invasive, reversible, and spatiotemporally controlled pH changes—ideal for modulating sensitive biological events such as amyloid fibrillogenesis and defibrillogenesis. To address the fundamental challenge of acid-base self-neutralization in simultaneous photoactivation systems, we propose a wavelength-orthogonal design that ensures sequential release of acids and bases using mutually non-interfering photocages (Scheme 1B). By precisely tuning the activation wavelengths, we can generate well-defined local pH gradients to control the state of amyloid proteins (Scheme 1C). We propose three photocage pairings for sequential light-controlled pH modulation (Scheme 2): • Blue and Green light: Coumarin-based photobase (blue) and BODIPY-based photoacid (green). • Green and Red light: Green light-activated BODIPY photobase and red light-responsive BODIPY photoacid. • Red and NIR light: Cyanine-3 photobase (red) and Cyanine-7 photoacid (NIR), expanding biological relevance for in vivo applications. This innovative approach will allow us to: • Control the initiation and inhibition of amyloid fibrillogenesis, • Induce reversible defibrillogenesis of mature fibrils, and • Establish a modular photochemical toolkit for light-controlled neurotherapeutics. The outcomes will establish a foundation for next-generation, non-invasive phototherapies targeting late-stage neurodegeneration.

Alzheimer’s disease, Amyloid-β, Wavelength-Selective, Photocages, Photoacid, Photobase