# Modulation of innate immunity in Alzheimer disease

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $239,850

## Abstract

Modulation of innate immunity in Alzheimer disease
Patients with Alzheimer’s disease (AD) develop deposits of abnormally aggregated amyloid β-protein (Aβ) and
abnormal aggregates (neurofibrillary tangles, NFTs) of hyperphosphorylated tau protein. Fibrillar Aβ deposits in
the brain are accompanied with activated microglia. Many lines of evidence support the notion that activated
microglia, innate immune cells in the central nervous system, play pivotal, dual roles in AD progression: either
clearing Aβ deposits by phagocytosis and promoting neuron survival and plasticity or releasing cytotoxic
chemicals, inflammatory cytokines, exacerbating Aβ load and neurodegeneration. Activating microglia with a
beneficial phenotype should have clinically vital importance in AD therapy and prevention. Aβ aggregates
activate microglia through certain toll-like receptors (TLRs) including TLR4. TLRs are a class of pattern-
recognition receptors in the innate immune system. One of the important roles of TLRs is to activate microglia in
response to pathogens and damaged host cells, and to clear pathogens, damaged tissues, and accumulated
wastes. Activation of microglia through certain TLRs can markedly boost ingestion and clearance of Aβ. Indeed,
treatments of AD mouse models with certain TLR agonists activates microglia and decreases cerebral Aβ
deposits, NFTs and improve cognitive deficits. However, prolonged exposure to certain TLR agonists, such as
lipopolysaccharide (LPS), induce hyporesponsiveness to subsequent TLR agonist challenge (endotoxin/TLR
tolerance), leading to immune paralysis. Because Aβ aggregates are a TLR agonist, we hypothesize that chronic
exposure of microglia to Aβ aggregates induces Aβ/TLR tolerance, leading to decreased clearance of Aβ
aggregates and reduced neuronal survival and plasticity in AD and its animal models. We found that an AD
mouse model is hyper-responsive to a TLR4 agonist, LPS, prior to cerebral Aβ deposition (a primed,
hypersensitive state) but hypo-responsive after cerebral Aβ deposition (tolerance). We found that certain
biomarkers of TLR tolerance are upregulated in an AD mouse model after the development of Aβ deposition in
the brain. Multiple immunomodulators can reverse LPS tolerance in monocytes. We hypothesize that such
immunomodulators enhance clearance of Aβ deposits and ameliorate cognitive deficits in an AD mouse model
(Aim 1) by reversing “LPS/Aβ tolerance” (Aim 2). This hypothesis will be tested by carrying out the following
specific aims: (Aim 1) to investigate the effects of an immunomodulator on AD-like pathology and cognitive
functions in an AD mouse model and (Aim 2) to investigate the effect of an immunomodulator on reversing LPS
tolerance. This study will serve as a proof of principle to determine if Aβ/TLR tolerance induced by Aβ deposition
can be reversed by certain immunomodulators leading to amelioration of AD-like pathophysiology. If successful,
this study will offer a new immunotherapeutic approach...

## Key facts

- **NIH application ID:** 9867616
- **Project number:** 5R21AG062179-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Ken-ichiro Fukuchi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $239,850
- **Award type:** 5
- **Project period:** 2019-02-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867616

## Citation

> US National Institutes of Health, RePORTER application 9867616, Modulation of innate immunity in Alzheimer disease (5R21AG062179-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9867616. Licensed CC0.

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