Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice
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
Nervous System Diseases | Neuroscience and Neurobiology
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.
UMCCTS funding, Alzheimer’s disease, IL18, inflammasome, neuroinflammation, seizures
DOI of Published Version
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
Proceedings of the National Academy of Sciences of the United States of America
Tzeng, TeChen; Hasegawa, Yuto; Iguchi, Risa; Cheung, Amy; Caffrey, Daniel R.; Thatcher, Elizabeth Jeanne; Mao, Wenjie; Germain, Gail; Tamburro, Nelsy DePaula; Okabe, Shigeo; Heneka, Michael T.; Latz, Eicke; Futai, Kensuke; and Golenbock, Douglas T., "Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice" (2018). Neurobiology Publications and Presentations. 231.