# Ligand discovery for delineating cholesterol homeostasis in the brain

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $39,125

## Abstract

Project Abstract: The PI and his investigation team at Emory aim to establish a productive and collaborative research
platform and acquire advanced research skills in Japanese host institution (NIRS/QST) to support the advancement
of the parent NIH award through the US-Japan Brain Research Cooperative Program (BRCP).
 Alzheimer’s disease (AD) is a long-term neurodegenerative disorder that ranks sixth in the leading cause of all
deaths in the United States and features amyloid β protein deposition and neurofibrillary tangles. At present, there are
no drugs available to halt or reverse disease progression, and all efforts to create such therapies have failed. Recent
studies have demonstrated that abnormalities of cholesterol homeostasis in the brain are strongly associated with
several neurodegenerative diseases, including AD. The CYP46A1 enzymatic conversion of brain cholesterol into 24S-
hydroxycholesterol is the major elimination mechanism to maintain brain cholesterol homeostasis. Disturbances in
CYP46A1 is implicated in the AD physiopathology. Therefore, pharmacological modulation of CYP46A1 represents
an attractive AD therapeutic approach. Positron emission tomography (PET) is capable of quantifying biochemical
processes in vivo, and a suitable CYP46A1 ligand would substantially improve our understanding of CYP46A1-
mediated cholesterol homeostasis under AD physiopathological conditions otherwise inaccessible by ex vivo
(destructive) analysis. Quantification of CYP46A1 in living AD brain by PET would provide the assessment of
distribution, target engagement and dose occupancy of new AD therapeutics. To date, no successful examples have
been demonstrated to image CYP46A1 for clinical use, representing a significant deficiency of our ability to study this
target in vivo. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational
imaging tool for AD.
 Through the administrative supplements for the U.S.-Japan Brain Research Cooperative Program, we will achieve
our goals through the following objectives: (1) To conduct collaborative research activities in the development of PET
ligands targeting CYP46A1 in the central nervous system and its implication in Alzheimer’s disease as the focus of
PI’s parent award; (2) To provide a training flatform to acquire advanced research skills, such as radiochemistry and
PET imaging studies, in the Japanese host institution (NIRS/QST) that could substantially benefit our existing parent
research; and (3) To establish a productive and sustainable working relationship and scientific dialog between Emory
and NIRS/QST for continued collaboration on mutually interested research topics that aligned with the NIA mission.

## Key facts

- **NIH application ID:** 10658329
- **Project number:** 3R01AG070060-03S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Steven H Liang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,125
- **Award type:** 3
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10658329

## Citation

> US National Institutes of Health, RePORTER application 10658329, Ligand discovery for delineating cholesterol homeostasis in the brain (3R01AG070060-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10658329. Licensed CC0.

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