Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 36, Pages 9002-9007Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1801802115
Keywords
Alzheimer's disease; neuroinflammation; inflammasome; IL18; seizures
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Funding
- National Center for Advancing Translational Sciences
- National Institute of Neurological Disorders and Stroke of NIH [UL1-TR001453, R01NS085215]
- Riccio Fund for Neuroscience
- University of Massachusetts Research Trust Fund
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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/PS1 Delta E9 (APP/PS1) mice, are completely protected from amyloidinduced AD-like disease, presumably because they cannot produce mature IL1 beta 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.
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