Date of Award

6-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Wei Li, PhD

Committee

Julio F. Cordero-Morales, PhD; Jianyang Du, PhD; Jianxiong Jiang, PhD; Francesca-Fang Liao, PhD

Keywords

Alzheimer’s disease; TRPC3; calcium ion channel; small molecule inhibitors

Abstract

Alzheimer's disease (AD) is a progressive neurological disorder characterized by extracellular β-amyloid (Aβ) plaques and intracellular tau tangles. The calcium (Ca2+) hypothesis of AD proposes that disrupted intracellular Ca2+ regulation underlies AD pathology, contributing to inflammation, oxidative stress, impaired autophagy, neurodegeneration, and cognitive dysfunction. Store-operated Ca2+ entry (SOCE) maintains ER Ca2+ stores, involving transient receptor potential canonical (TRPC) and Orai channels. Specifically, we speculated that dysregulated functions of TRPC3 contribute to the pathogenesis of AD. We believe that targeting TRPC3 with a pharmacologically feasible agent could prove beneficial in halting cognitive decline. We previously reported compound JW-65, a novel, metabolically stable, brain-penetrative, selective, and safe TRPC3 inhibitor that can directly bind to the TRPC3 protein. We utilized JW-65 as a tool molecule and identified TRPC3 as a unique member of the TRPC family that contributes to the development of AD via the Aβ cascade, in contrast to the predominantly protective role of TRPC6. Preliminary animal studies performed on PS19 mice, a widely studied mouse model of tau pathology, also demonstrated the therapeutic efficacy of JW-65. This finding highlights TRPC3 as a promising therapeutic target for AD. Considering the promising efficacy of JW-65 and the potential for TRPC3-targeted therapy, a panel of JW-65 analogs were synthesized, and their potency and selectivity were characterized. This approach aims to enhance the therapeutic options available for AD treatment.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0002-3202-2402

DOI

10.21007/aetd.cghs.2024.0006

Additional Files
2024-006-Wang-AETD-pdfA.pdf (6945 kB)
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