# Transcriptional Control of Neuroinflammation in Alzheimer's Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $844,476

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder of aging, affecting about 44 million
people worldwide with 5.5 million in the U.S. Amyloid plaques in the brain, one of the pathological hallmarks of
AD, consist of fibrillary forms of amyloid β peptide-40 (Aβ-40) and amyloid β peptide-42 (Aβ-42) produced from
amyloid precursor proteins by sequential cleavage, and are crucial for the neuro-pathogenesis of AD. Despite
major drug development efforts targeting Aβ peptide cleavage and processing, nearly all experimental drugs
tested for AD thus far have failed to show significant efficacy. New therapeutic strategies are urgently needed
to offer new prevention and treatment opinions for AD that represents a major unmet medical need. Aβ
aggregates induce oxidative stress and inflammation leading to microglia activation and neurodegeneration in
the brain. This process is fueled by pro-inflammatory cytokines such as IL-17, IL-21, IL-22, and IL-23, secreted
by CD4+ T-helper 17 (Th17) cells, which are found to be elevated in the peripheral blood of individuals with AD
dementia and mild cognitive impairment (MCIAD) over normal aging control subjects. Notably, we discovered
that expression of Rorc, a major transcription factor of microglia, and target genes Il18, Nos2, and Casp4 are
markedly increased in the brain of AD and MCIAD patients over healthy aging controls, and Rorc up-regulation
is more profound in female than male AD patients. We further found that IL-17 and TNFa, produced by Th17
cells, induce transcriptional expression of Rorc, Il6, Il18, Il23, and Tnfa in mouse microglia. Since IL-23 can
induce pathogenic Th17 cell development, we postulate that Th17 and microglial cells likely act in a positive
feedback loop to promote inflammation contributing to AD pathogenesis. Importantly, our new bromodomain
inhibitor that selectively targets major transcription regulator BRD4 effectively inhibits transcription of Il17, Il21,
Il22, Rorc and Il6 in mouse Th17 cells, and Il6, Tnfa, Il18, Il23, Nos2, and Casp4 in mouse primary microglia.
Furthermore, MS402 blocks over-production of Th17 cells in experimental autoimmune encephalomyelitis in
mice, a model mimicking the neuroinflammatory disorders in humans. Our results strongly suggest a promise
of our Th17/microglia immunomodulators as a new treatment for AD. Motivated by our favorable findings, in
this study, we will (1) investigate the mechanisms of transcriptional regulation of Th17 and microglial cells in
AD pathogenesis; (2) develop and characterize Th17 and microglial immunomodulators for AD treatment; and
(3) investigate in vivo therapeutic efficacy of Th17 and microglial immunomodulators in AD mouse models.

## Key facts

- **NIH application ID:** 10213328
- **Project number:** 1R01AG072562-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Dongming Cai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $844,476
- **Award type:** 1
- **Project period:** 2021-06-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213328

## Citation

> US National Institutes of Health, RePORTER application 10213328, Transcriptional Control of Neuroinflammation in Alzheimer's Disease (1R01AG072562-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213328. Licensed CC0.

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