Author ORCID Identifier

https://orcid.org/0000-0003-0013-6912

Date of Award

Fall 2024

Document Type

Thesis (Ph.D.)

Department or Program

Biochemistry and Cell Biology

First Advisor

Ta Yuan Chang

Abstract

Cholesterol dysregulation is implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Niemann-Pick type C disease (NPCD). This study focused on evaluating the potent ACAT1 inhibitor, F26, as a therapeutic strategy for NPCD. F26 demonstrated superior ACAT1 inhibition and efficacy compared to the previously studied inhibitor, F12511, both in vitro and in vivo. Notably, F26 exhibited enhanced pharmacokinetic properties, including prolonged duration of action and better brain retention, making it a more promising candidate for treating neurodegenerative diseases.

F26 was encapsulated in a liposome-based nanoparticle system, DSPE-PEG2000 with phosphatidylcholine (PC), for enhancing its solubility and blood-brain barrier (BBB) permeability. F26 showed significantly better BBB penetration and retention compared to F12511, further highlighting its therapeutic advantage. Despite these promising results, neither F12511 nor F26 treatments significantly improved NPCD pathology such as foamy macrophage accumulation and Purkinje cell (PC) degeneration in Npc1nmf mice after 14- and 46-day regimens, underscoring the need for more precise treatment design and earlier intervention for optimal outcomes.

In a parallel approach, we also tested AAV9-Acat1 miRNA to inhibit ACAT1 in the brain, but the partial inhibition achieved through direct cerebellar injection did not significantly alter disease progression in Npc1nmf mice. This further emphasizes the importance of both complete target engagement and effective delivery methods in addressing the complex pathology of NPCD.

Our findings demonstrate the potential of F26 as a superior ACAT1 inhibitor, while also highlighting the importance of early intervention and optimized delivery strategies for therapeutic success in NPCD and other neurodegenerative diseases.

Download

Share

COinS