# Altering immune tolerance in Alzheimer disease

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

## Abstract

Altering immune tolerance in Alzheimer disease
Amyloid plaques composed of deposits of abnormally aggregated amyloid β-protein (Aβ) and neurofibrillary
tangles (NFTs) consisting of abnormal aggregates of hyperphosphorylated tau protein in the brain are two main
pathological changes in patients with Alzheimer’s disease (AD). Amyloid plaques and NFTs are accompanied
with chronic inflammation characterized by activated microglia and increased cytokines. 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 pathways that can modulate the progression of the
vast majority of AD cases for development of preventive and therapeutic measures. 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 and inflammatory cytokines, exacerbating Aβ load and causing
neurodegeneration. Activating microglia with a beneficial phenotype should have clinically vital importance in AD
therapy and prevention. C-type lectin receptors including dectin-1 and toll-like receptors (TLRs) including TLR4
are classes of pattern-recognition receptors in the innate immune system. One of the important roles of these
receptors 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 activate
microglia, decrease cerebral Aβ deposits and NFTs, and improve cognitive deficits. However, prolonged
exposure to certain TLR agonists, such as lipopolysaccharide (LPS), induce hyporesponsiveness to subsequent
TLR agonist challenges (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 becomes hypo-responsive to a TLR4 agonist, LPS, after
cerebral Aβ deposition (tolerance). Activation of dectin-1 signaling reverses or counteracts LPS tolerance in
monocytes. We hypothesize that dectin-1 signaling enhances clearance of Aβ deposits and ameliorates cognitive
deficits in an AD mouse model by counteracting and reversing “LPS/Aβ tolerance”. This hypothesis will be tested
by carrying out the following aims. In Aim 1, we will produce a dectin-1-deficient (clec7a-/-) AD mouse model and
determine its effects on AD-pathology and behavioral functions. In Aim 2, we will inject a dectin-1 ligand into the
hippocampi of dectin-1-defic...

## Key facts

- **NIH application ID:** 9979733
- **Project number:** 5R21AG064811-02
- **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:** 2019-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979733

## Citation

> US National Institutes of Health, RePORTER application 9979733, Altering immune tolerance in Alzheimer disease (5R21AG064811-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979733. Licensed CC0.

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