# Inflammasome activation in modulation of Alzheimer's Disease by alcohol

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $428,125

## Abstract

Neuroinflammation has emerged as a critical feature of Alzheimer’s disease (AD) pathogenesis
and alcohol-related brain damage. Previous studies, including our own, have shown that innate
immune signaling pathways particularly NLRP3 inflammasome activation play an important role
both in AD and in alcohol-induced neuroinflammation. However, the influence of heavy alcohol
use on AD remains largely unknown. The focus of our research is to evaluate the effect of
excessive alcohol consumption on the development and progression of AD and identify critical
molecular pathways that may provide therapeutic targets. Activation of the multiprotein complex,
inflammasome, by PAMPs or DAMPs involves two signals: first, TLR-mediated activation that
increases pro-IL-1ß and second, NLRP-mediated inflammasome assembly and caspase-1
activation that cleaves pro- IL-1ß to mature IL-1ß. We previously showed increased IL-1ß
production as a result of NLRP3/ASC inflammasome and caspase-1 activation in the brain after
chronic alcohol feeding. In the APP/PS1 and Tau22 mouse models of AD, caspase-1 activity and
IL-1ß production is dependent on NLRP3 and NLRP3 inflammasome activation drives Aß and tau
pathology. Based on these observations, we hypothesize that chronic alcohol exposure
accelerates and exacerbates AD features. We postulate that chronic alcohol-induced
NLRP3/ASC inflammasome activation contributes to the development and progression of AD via
amplified neuroinflammation. The aims of this study are 1. To characterize the effect of long-term
and excessive alcohol consumption on AD features using APP/PS1 and Tau22 mice 2. To
delineate the role of NLRP3/ASC inflammasome components in alcohol-mediated
neuroinflammation in AD mice 3. To evaluate the contribution of IL-1 signaling pathway in
inflammasome-mediated neuroinflammation in response to alcohol consumption in AD mice.
These experiments will provide novel insight on the role of alcohol-mediated inflammasome
activation in the development and progression of AD and evaluate preclinical interventions that
interrupt inflammasome-mediated neuroinflammation by targeting key pathogenic pathways
discovered in this research.

## Key facts

- **NIH application ID:** 10471334
- **Project number:** 5R01AG072899-03
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Douglas T Golenbock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $428,125
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471334

## Citation

> US National Institutes of Health, RePORTER application 10471334, Inflammasome activation in modulation of Alzheimer's Disease by alcohol (5R01AG072899-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10471334. Licensed CC0.

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