# Role of inflammasomes in Alzheimer's Disease

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $1,019,436

## Abstract

PROJECT SUMMARY/ABSTRACT
Neuroinflammation is an important component of Alzheimer's disease (AD). However, the molecular
mechanism by which inflammation modulates AD progression is not defined. We discovered that beta-amyloid
1-42 activates NLRP3 inflammasomes and that AD patients uniformly have evidence of activated
inflammasomes in their brains. To test the role of NLRP3 inflammasomes in AD, we bred APP/PS1 mice (an
amyloid-based murine model of AD) into NLRP3, ASC, or caspase-1 KOs (the three proteins comprising the
NLRP3 inflammasome) and observed that these mice were completely protected from numerous AD features
including learning/memory deficits and abnormalities in long-term potentiation.
 NLRP3 inflammasomes regulate the expression of IL-1beta and IL-18, two highly proinflammatory cytokines
abundantly produced in microglial cells; in addition, astrocytes are strong expresses of pro-IL-18. IL-1beta is
abundant in microglial cells on the periphery of amyloid plaques and can cause fever, a strong acute phase
response, sepsis syndrome, and pyroptotic cell death. IL-18 is a member of the IL1 superfamily. Unlike IL-
1beta, IL-18 does not activate NF-kappaB or have pyrogenic activity. It is unknown if IL-1beta or IL-18
reduction was responsible for the protective phenotype in inflammasome-deficient APP/PS1 mice. We
generated IL-18KO/APP/PS1 mice and, surprisingly, these mice developed a lethal seizure disorder, which
was completely reversed by levetiracetam therapy. This is highly relevant as epidemiologic studies suggest
that almost two-thirds of AD patients have seizures at some point during the course of their disease.
 In Aim 1, we will examine the role of inflammasome-dependent pyroptosis in microglial cells in the
pathogenesis of AD using transgenic mice in which the inflammasome has been specifically deleted from
microglial cells on an APP/PS1 background. We will also test APP/PS1 mice deficient for Gasdermin D (a
caspase-1 substrate and the final effector molecule of pyroptosis). In Aim 2, we will examine if IL-18
counterbalances the proepileptic effects of IL-1beta in AD-related seizures. We will use a genetic approach
(deleting IL-18 in other AD mouse models) as well as a pharmacological approach (an IL-1beta loss-of-function
approach) in IL-18KO/APP/PS1 mice and assess animals for seizures. In Aim 3, we will determine the role of
IL-18 in reducing neuronal network activity and modulating synaptic transmission. We will identify the types of
synapses that are dysregulated in IL-18KO/APP/PS1 mice by performing morphological and
electrophysiological studies as well as biochemical analysis using immunohistochemistry. We will specifically
examine the role of microglial IL-18 using a floxed IL-18 transgenic mouse line. Successful completion of these
Aims will elucidate the role of inflammasome-generated cytokines in AD, and could result in novel translational
approaches designed to specifically halt the inflammation that drives AD, as well ...

## Key facts

- **NIH application ID:** 10219139
- **Project number:** 5R01AG059752-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Douglas T Golenbock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,019,436
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219139

## Citation

> US National Institutes of Health, RePORTER application 10219139, Role of inflammasomes in Alzheimer's Disease (5R01AG059752-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10219139. Licensed CC0.

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