[en] 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/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β 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.
Disciplines :
Neurology
Author, co-author :
Tzeng, Te-Chen; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605
Hasegawa, Yuto; Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604 ; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01604
Iguchi, Risa; Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604 ; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01604 ; Department of Cellular Neurobiology Graduate School of Medicine, University of Tokyo, 113-0033 Tokyo, Japan
Cheung, Amy; Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604 ; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01604
Caffrey, Daniel R; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605
Thatcher, Elizabeth Jeanne; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605
Mao, Wenjie; Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604 ; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01604
Germain, Gail; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605
Tamburro, Nelsy DePaula; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605
Okabe, Shigeo; Department of Cellular Neurobiology Graduate School of Medicine, University of Tokyo, 113-0033 Tokyo, Japan
HENEKA, Michael ; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605 ; Institute of Innate Immunity, University Hospitals, University of Bonn, 53127 Bonn, Germany
Latz, Eicke; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605 ; Institute of Innate Immunity, University Hospitals, University of Bonn, 53127 Bonn, Germany
Futai, Kensuke; Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, Kensuke.Futai@umassmed.edu Douglas.Golenbock@umassmed.edu ; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01604
Golenbock, Douglas T; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, Kensuke.Futai@umassmed.edu Douglas.Golenbock@umassmed.edu
Foundation for the National Institutes of Health Foundation for the National Institutes of Health
Funding text :
ACKNOWLEDGMENTS. We thank Chunxing Yang and Zuoshang Xu for providing the home cage system and Melanie Trombly for editing the manuscript. Research reported in this publication was supported in part by National Center for Advancing Translational Sciences and National Institute of Neurological Disorders and Stroke of NIH Grant UL1-TR001453 (to D.T.G.), Grant R01NS085215 (to K.F.), and the Riccio Fund for Neuroscience (D.T.G. and K.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. In addition, the work was partially funded by the University of Massachusetts Research Trust Fund. The authors have no competing financial interests.
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