# The role of 25-hydroxycholesterol in modulating ApoE-dependent Alzheimer disease-related pathogenesis

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2021 · $150,765

## Abstract

The goal of this mentored career development award is to facilitate the candidate’s transition to independence
as a physician-scientist studying molecular mechanisms of neuroinflammation and neurodegeneration. The
candidate is a MD/PhD neurologist with a background in neurodegenerative disease research. The award will
help the candidate achieve his short-term goal, to gain research experience in the molecular pathogenesis of
neuroimmune activation and neurodegeneration in models of Alzheimer disease (AD)-like pathology and
facilitate his transition to an investigator with an independent laboratory. The award will also help position the
candidate to achieve his long-term goal of becoming a successful and productive physician-scientist and a leader
in academic neurology. The environment in which the proposed research will be conducted is outstanding. The
candidate’s primary mentor, Dr. David Holtzman, is an internationally respected scientist and neurologist with a
proven track record of excellence in training junior faculty. The candidate’s career development plan includes
structured co-mentorship from Dr. John Morris, also an internationally respected neurologist and clinician-
scientist, who will supervise the candidate’s clinical training and development of clinical research skills. Drs.
Holtzman and Morris have a track record of co-mentoring numerous junior faculty to successful independent
research careers in neurology. Didactic learning, presentation of work at scientific meetings, and rigorous training
in the responsible conduct of research will ensure a balanced development. The proposed research will examine
the role of 25-hydroxycholesterol (25-HC) in modulating the neuroimmune response to ApoE-dependent amyloid
pathology and tau-mediated neurodegeneration. Multiple lines of evidence suggest that activation of immune
mediators is a critical regulator of AD pathology. However, the exact role that microglia play in modulating AD
pathogenesis is still difficult to parse, partly due to discrepant effects of microglial function in models of
amyloidosis and tauopathy. Microglial response to amyloid and tau deposition is dependent on apolipoprotein E
(ApoE) as evidenced by experiments where ApoE expression is genetically deleted. 25-HC is produced exclusively
by microglia, is a potent modulator of microglial response, has been implicated in the pathogenesis of autoimmune
neurological disease and modulates the production of ApoE. The goal of this project is to test the hypothesis that
microglial production of 25-HC modulates ApoE-dependent neuroinflammatory responses and neurodegeneration in
mouse models of amyloid and tau deposition. Clarifying the role of 25-HC and ApoE in these processes will provide
insights into AD pathobiology and ultimately should point towards novel therapeutic targets that can be leveraged
to treat AD and related dementias. This career development award is an ideal mechanism to provide the
candidate with valuable resear...

## Key facts

- **NIH application ID:** 10232240
- **Project number:** 5K08AG068611-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Justin Matthew Long
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $150,765
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232240

## Citation

> US National Institutes of Health, RePORTER application 10232240, The role of 25-hydroxycholesterol in modulating ApoE-dependent Alzheimer disease-related pathogenesis (5K08AG068611-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10232240. Licensed CC0.

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