# Role of the microglial immune-oxysterol 25-hydroxycholesterol in mediating neuroinflammation and neurodegeneration in the P301S tau transgenic mouse model of Alzheimer's disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $466,366

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer disease (AD) is the most common neurodegenerative disorder characterized by neuroinflammation
associated with amyloid plaques and tau-containing neurofibrillary tangles in the brain as well as severe
neurodegeneration, neuroinflammation and lipid accumulation. The apolipoprotein E (APOE) genotype is by far
the most powerful genetic risk factor for late-onset AD and is thought to play an important role in
neuroinflammation and lipid metabolism. Pathological activation of microglia and astrocytes contribute
substantially to the loss of neurons and synapses and lipid dysfunction in AD and related dementias (ADRD).
Despite an important pathogenic role for microglia in tau-mediated neurodegeneration, the specific microglial
mediators of neuroinflammation and neurodegeneration are poorly understood. Our lab has recently
demonstrated that the microglial immune-oxysterol 25-hydroxycholesterol (25HC) augments the production of
the proinflammatory cytokine, IL-1b, in an APOE-isoform dependent manner (E4>E3). Cholesterol 25-
hydroxylase (CH25H), the enzyme that synthesizes 25HC is upregulated in AD and PS19 brain tissue as well
as in disease-associated microglia (DAM). We have preliminary evidence that 25HC directly contributes to the
age-dependent neurodegeneration observed in PS19 mice and regulates cholesterol metabolism in astrocytes.
We hypothesize that 25HC synthesized and secreted by activated microglia drives tau-dependent
neuroinflammation and neurodegeneration via its effects in regulating cholesterol metabolism. We will test this
hypothesis as follows – In Aim 1, we will determine the importance of Ch25h in mediating tau-dependent
neuroinflammation and neurodegeneration. In Aim 2, we will determine the role of Ch25h/25HC in mediating
the deleterious effects of APOE4 on tau-dependent neuropathology. In Aim 3, we will determine whether and
how 25HC alters cholesterol metabolism to reduce neuronal viability. Successful completion of this project may
enable the development of novel therapeutic strategies towards ADRD.

## Key facts

- **NIH application ID:** 10837082
- **Project number:** 5R01AG081419-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** ANIL G CASHIKAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,366
- **Award type:** 5
- **Project period:** 2023-05-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837082

## Citation

> US National Institutes of Health, RePORTER application 10837082, Role of the microglial immune-oxysterol 25-hydroxycholesterol in mediating neuroinflammation and neurodegeneration in the P301S tau transgenic mouse model of Alzheimer's disease (5R01AG081419-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10837082. Licensed CC0.

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