# Microglia Activation and TLR-induced Neurodegeneration by Alcohol Promotes Progression of Alzheimer Pathology

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $388,750

## Abstract

Abstract
Chronic heavy or binge alcohol use is associated with dementia and increased risk for Alzheimer's disease (AD),
though mechanisms connecting the disease pathologies have not been identified. AD pathology follows a
temporal progression of proinflammatory signaling in brain with Aβ deposition, tau fibril formation, synapse loss,
neurodegeneration, and cognitive decline. We find increased AD pathology proteins Aβ1-42 and phosphorylated
(p)-tau-181 in human alcohol use disorder (AUD) brain and after chronic binge ethanol during early life in the 3x-
Tg-AD mouse model. Toll-like Receptor (TLR) proinflammatory signaling is thought to precede gross pathology
in AD, and is a prominent feature of AUD. We find AUD in young individuals is associated with AD protein
accumulation, and chronic binge ethanol treatment in 3x-Tg-AD mice causes persistent upregulation of
proinflammatory genes that correlated strongly with levels of neurotoxic Aβ1-42 and p-tau-181 protein. Thus, we
hypothesize ethanol promotes AD neurotoxic protein pathology by enhancing proinflammatory signaling.
Microglia have emerged as mediators of AD pathology, contributing to Aβ plaque formation, tau propagation,
synapse loss and possibly neurodegeneration. Microglial change phenotype (e.g. resting, phagocytic,
proinflammatory, pruning, or neurotoxic) and microglial activation is thought to precede and promote AD
pathology. Human GWAS as well as human and AD mouse single nuclei RNA sequencing (snRNA-seq) have
identified AD microglia as altered, having increased C1q (pro-synaptic pruning) and reduced resting state
markers (e.g. Tmem119). In human AUD brain, we find reduced resting state microglia (reduced Tmem119)
with proinflammatory microglia. Further, we find chronic binge ethanol in vivo persistently increases C1q and
proinflammatory cytokines mirroring AD. Thus, we hypothesize proinflammatory microglial activation by
chronic heavy/binge ethanol promotes AD Aβ and tau pathology, synapse loss and neurodegeneration.
This hypothesis will be tested in human AD post-mortem brain (Aim 1), and the 3x-Tg-AD mouse model (Aim 2)
that features progressive Aβ and tau pathology.
Apoptotic neuronal cell death is a feature of AD pathology thought to contribute to irreversible cognitive decline.
We find binge ethanol increases neurodegeneration in brain regions known to have neuronal loss in AD such as
prefrontal cortex (PFC) and hippocampus. Our studies implicate proinflammatory Toll-like Receptor (TLR)
activation and microglial to neuronal interactions that lead to apoptotic neuronal cell death. We find chronic
binge ethanol increases HMGB1-TLR4 signaling to activate microglia. Proinflammatory microglia secrete the
miRNA let-7b that we found activates TLR7 in neurons. Let-7b-TLR7 signaling in neurons induces apoptotic
neuronal cell death via the TNF-receptor superfamily apoptosis-inducing ligand (TRAIL). TLR4, HMGB1, let-7
and TRAIL have each been implicated in AD pathology. However, a link in ...

## Key facts

- **NIH application ID:** 10132135
- **Project number:** 1R01AA028924-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** FULTON T CREWS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 1
- **Project period:** 2020-09-20 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132135

## Citation

> US National Institutes of Health, RePORTER application 10132135, Microglia Activation and TLR-induced Neurodegeneration by Alcohol Promotes Progression of Alzheimer Pathology (1R01AA028924-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132135. Licensed CC0.

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