Title

Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice

UMMS Affiliation

Department of Neurobiology; Department of Medicine, Division of Infectious Diseases and Immunology; Brudnick Neuropsychiatric Research Institute; Futai Lab; Graduate School of Biomedical Sciences, Program in Neuroscience; Graduate School of Biomedical Sciences, MD/PhD Program

Publication Date

2018-09-04

Document Type

Article

Disciplines

Nervous System Diseases | Neuroscience and Neurobiology

Abstract

Alzheimer's disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1DeltaE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1beta or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD.

Keywords

UMCCTS funding, Alzheimer’s disease, IL18, inflammasome, neuroinflammation, seizures

DOI of Published Version

10.1073/pnas.1801802115

Source

Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):9002-9007. doi: 10.1073/pnas.1801802115. Epub 2018 Aug 20. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

30127003

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