Research Projects

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral deterioration. One of its defining hallmarks is the formation of amyloid fibrils—insoluble aggregates primarily composed of amyloid-β (Aβ) peptides. The aggregation process and fibril stability are strongly pH-dependent: acidic environments promote fibrillogenesis, while basic conditions can destabilize and even disassemble mature fibrils. While existing phototherapeutic interventions mainly focus on early-stage aggregation inhibition, strategies for reversible defibrillogenesis—the breakdown of preformed fibrils—are underexplored. To address this challenge, we propose a light-triggered, wavelength-selective platform for spatiotemporal pH modulation using photoacids and photobases. These molecules exhibit light-induced shifts in acidity or basicity, enabling reversible, non-invasive control over biological processes. Our approach will allow precise initiation, inhibition, and reversal of amyloid fibrillogenesis using light as an external stimulus. A key innovation is the development of wavelength-orthogonal systems to prevent unwanted self-neutralization when activating both acid and base pathways. We will implement both multichromophoric (different chromophores for blue, green, red, NIR light) and monochromophoric (single chromophore with wavelength-selective pathways) designs to achieve controlled pH modulation. The multichromophoric systems will include: • Blue/Green: Coumarin photobase and BODIPY photoacid, • Green/Red: BODIPY-based acid-base pairs, • Red/NIR: Cyanine-3 and Cyanine-7 systems for deep tissue applications. The monochromophoric systems will build upon our recently developed hydroxanthene-based platform, extended to hydroacridine and BODIPY cores to enable blue-to-red selective releases. These tailored systems will be used to: • Control the onset and inhibition of Aβ aggregation, • Trigger reversible disassembly of mature amyloid fibrils, Demonstrate programmable, light-responsive pH gradients in live-cell-compatible environments. Our preliminary work has already shown controlled photorelease of valproic acid to inhibit Aβ aggregation. However, the new systems aim to advance this to bidirectional, wavelength-selective pH modulation, enabling both inhibition and disassembly of fibrils—an unmet goal in AD research. • This proposal is grounded in a multidisciplinary framework, integrating photochemistry, supramolecular design, and neurobiology. The outcomes are expected to: • Enable light-controlled therapeutic precision in protein aggregation disorders, • Offer non-toxic, tunable alternatives to traditional drug regimens, • Extend applicability to real-time imaging, diagnostics, and smart biomaterials. By leveraging innovations in photoremovable protecting groups (PRPGs) and addressing their limitations (e.g., UV-dependence, low penetration), our strategy pioneers a next-generation photoneurotherapeutic toolkit. It aligns with emerging interests in dynamic, responsive systems for biological regulation, holding promise for broad translational impact in Alzheimer’s disease and beyond.