Date of Award

Winter 12-5-2024

Document Type

Thesis (Ph.D.)

Department or Program

Biochemistry and Cell Biology

First Advisor

Ta Yuan Chang, PhD

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease that significantly impacts nearly 7 million people in the United States. AD is characterized by the deposition of amyloid beta (Ab) plaque, tau neurofibrillary tangles (NFTs), lipids granules, and neuroinflammation. Age and apolipoprotein E4 (APOE4) are the two biggest risk factors for AD. Recent AD therapeutic development has mostly benefited the patient population with milder symptoms while causing serious side effects in APOE4 carriers, leaving the most impacted patients’ group - aged APOE4 carriers with no treatment option. With the increasing aging population, there is an urgent need for a therapy that works in aging and APOE4 carriers.

Acyl-coenzyme A (CoA):cholesterol acyltransferase 1 (ACAT1) is a promising therapeutic target for AD and has a track record of demonstrated efficacy against multiple AD models. Polymorphisms in the ACAT1 gene are associated with increasing AD risk. ACAT1 is responsible for intracellular cholesterol storage by converting cholesterol to cholesteryl ester (CE). In AD brains of human patients and mouse models, CE increases by almost 2-fold, and in APOE4 postmortem human brain tissue, CE significantly increases. Together, increasing evidence supports increased ACAT1 activity in disease conditions. Additionally, in AD and a few other neuroinflammation models, ACAT1 gene expression is significantly elevated. As we previously demonstrated in our laboratory that ACAT1 inhibition is beneficial in the amyloid and tau model of AD, as well as ameliorating neuroinflammation in lipopolysaccharides induced model, I investigated the effect of ACAT1 inhibition in aging and APOE4 mice model in my thesis work.

In Chapter 2, I present published results on the effect of ACAT1 inhibition on human HMC3 microglia loaded with cholesterol-rich myelin debris as an in vitro aging model. I show that myelin debris-loaded microglia lead to increased CE biosynthesis in intact cells, while the change in TAG biosynthesis rate is minimal and insignificant. Treatment of myelin debris-loaded HMC3 cells increases ABC transporter A1 (ABCA1) gene expression and protein content in a liver X receptor (LXR)- dependent manner.

In Chapter 3, I demonstrate that in APOE4 primary microglia, ACAT1 inhibition reduces CE-rich lipid droplets while increasing ABCA1 protein expression. In LPS-induced APOE4 primary microglia, ACAT1 inhibition dampens NFkB activation in a Toll-like receptor 4 (TLR4) dependent manner. In vivo, ACAT1 inhibition using ACAT1 inhibitor F12511 lipid-based nanoparticle system comprised of phosphatidylcholine (PC) and DSPE-PEG2000 reduce proinflammatory response, as well as TLR4 protein content in aged (16-20 months old) APOE3 and APOE4 mice. The effect is less significant in adult (9 months old) mice.

The results from my thesis suggest that ACAT1 inhibition is a novel therapeutic strategy for aging and APOE4 carriers in AD. Besides ACAT1 inhibitor’s ability to ameliorate amyloid and tau pathology, ACAT1 inhibition alters cholesterol trafficking and lipid raft to alter immune receptors signaling and dampen neuroinflammation while upregulating cholesterol efflux to reestablish cholesterol homeostasis in aging and APOE4 model.

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