# Nanoparticles encapsulating a potent cholesterol storage inhibitor as a novel therapeutic to treat Alzheimer's disease > **NIH NIH F31** · DARTMOUTH COLLEGE · 2020 · $45,520 ## Abstract Abstract Amyloid plaque and tau neurofibrillary tangles are the characteristic hallmarks of Alzheimer’s disease (AD). Recent failed clinical trials focused on targeting secretases involved in the amyloidogenic pathway, which is responsible for forming amyloid plaques. These and other failed trials point to the need for identifying novel target(s) that benefit AD in multiple ways, including the reduction of plaque and tangle production, and the enhanced clearance of misfolded tau, oligomeric amyloid beta (Ab) peptides and other toxins. The brain needs cholesterol to maintain vital functions and the dysregulation of cholesterol in the brain has been suggested to play an important role in AD. A small amount of cholesterol is stored away as cholesterol esters by the enzyme Acyl-CoA:cholesterol acyltransferase1 (ACAT1); however, cholesterol esters cannot substitute the function of cholesterol. Dr. TY Chang’s lab and others have shown that, in mouse models of amyloidopathy and tauopathy, ACAT1 blockage (A1B) provides more cholesterol to brain cells such that cells can fight AD by reducing Ab and misfolded tau and improves memory performance. Mechanistic studies suggest that A1B mainly acts by increasing the clearance of Ab oligomers in microglia, and by increasing the degradation of tau in neurons. These studies suggest that A1B is a promising new therapeutic to treat AD. Compound X is an ACAT1 specific small molecule inhibitor that passed Phase I Clinical Safety Test for treating cardiovascular disease; however, whether Compound X can cross the blood brain barrier to reach the brain interior is unknown. This training plan proposes to test the efficacy of several delivery methods to deliver Compound X as nanoparticles (Nanoparticle X) to the mouse brain. As an option, to increase the bioavailability and half-life of Compound X and to better target the brain, the PEGylated nanomicelle used will be tagged with a neuronal specific tag. Aim 1 will determine the short- and long-term efficacy of Nanoparticle X in inhibiting ACAT activity in the CNS. Wildtype mice will be treated with Nanoparticle X by oral, IP or IV administration and sacrificed at various time points. Aim 2 will test the efficacy of Nanoparticle X, delivered to mice by the optimal method, in ameliorating amyloidopathy/tauopathy and cognitive deficits. An AD mouse model will be treated with Nanoparticle X at asymptomatic, early- and late-symptomatic stages. Ab and tau will be assessed by ELISA and histological methods. Memory improvement will be assessed by a fear conditioning behavioral task. This training plan will determine if ACAT inhibitors encapsulated in nanomicelles are a potential therapy for AD. I have accumulated data in cell culture and in vivo that strongly suggest feasibility. I will continue to be under the guidance of my sponsor team, Drs. Chang and Havrda, and collaborators, Drs. Hoopes, Sporn, and Maurer. I will follow the detailed training plan and take relevant course... ## Key facts - **NIH application ID:** 9898156 - **Project number:** 5F31NS110317-02 - **Recipient organization:** DARTMOUTH COLLEGE - **Principal Investigator:** Adrianna De La Torre - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $45,520 - **Award type:** 5 - **Project period:** 2019-03-08 → 2021-03-07 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9898156 ## Citation > US National Institutes of Health, RePORTER application 9898156, Nanoparticles encapsulating a potent cholesterol storage inhibitor as a novel therapeutic to treat Alzheimer's disease (5F31NS110317-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9898156. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*