# Role of MyD88 signaling in systemic inflammation and Alzheimer disease

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $464,553

## Abstract

Project Summary / Abstract
The main pathological changes found in patients with Alzheimer’s disease (AD) are extracellular amyloid β (Aβ)
deposits in the brain parenchyma (amyloid plaques) and abnormal aggregates of hyperphosphorylated tau
protein in brain neurons (neurofibrillary tangles, NFTs). Amyloid plaques and NFTs are accompanied with chronic
inflammation characterized by activated microglia and increased levels of cytokines. Except a small subset of
early-onset familial AD cases, the causes for the vast majority of AD cases are unknown and satisfactory
therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the
molecular mechanisms that increase the risk for the vast majority of AD cases and to develop the preventive and
therapeutic measures. Systemic inflammation promotes AD progression and even initiates microglial activation
and neurodegeneration. Indeed, recent genetic studies on late-onset AD have identified about a dozen genetic
risk variants that are highly expressed in microglia and involved in innate immune responses, highlighting the
importance of immune responses, particularly activated microglia, in the pathogenesis of late-onset AD. Aging
is the largest known risk factor for AD and is characterized by chronic, systemic inflammation (inflamm-aging).
Systemic inflammation caused by certain bacterial and viral infections is a strong risk factor of dementia, also.
Additionally, our preliminary data indicate that activation of NLRP3 inflammasome through the MyD88 signaling
pathway in microglia in the central nervous system (CNS) plays essential roles in the AD pathogenesis. In Aim
1, we will produce a microglia specific MyD88 deficiency in AD mouse models during aging and determine their
effect on Aβ and tau pathology and cognitive function. We further hypothesize that microglial MyD88 signaling
plays a predominant role in accelerating brain Aβ and tau pathology and neuroinflammation, which are induced
by chronic, systemic inflammation, in AD mouse models during aging. In Aim 2, we will determine the effects of
systemic LPS treatment on Aβ and tau pathology and cognition in AD mouse models with brain and peripheral
immune cell-specific MyD88 deficiency. In Aim 3, we will determine the age and sex dependent effects of LPS
treatment on NLRP3 inflammasome activation as disease mechanisms in the brain/microglia-specific and
peripheral immune cell-specific MyD88 deficient AD mouse models. Our hypothesis is that LPS-induced
systemic inflammation causes NLRP3 inflammasome activation in microglia via MyD88 signaling, leading to
exacerbation of AD-like pathophysiology in AD mouse models. The long term goals are to determine the role of
microglial MyD88/NLRP3 inflammasome signaling in the AD pathogenesis, to elucidate the molecular
mechanism underlying the increased AD risk associated with systemic inflammation and to develop new
preventive and therapeutic strategies for AD.

## Key facts

- **NIH application ID:** 10314883
- **Project number:** 1R01AG069447-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Ken-ichiro Fukuchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $464,553
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314883

## Citation

> US National Institutes of Health, RePORTER application 10314883, Role of MyD88 signaling in systemic inflammation and Alzheimer disease (1R01AG069447-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10314883. Licensed CC0.

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