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Proc Natl Acad Sci U S A ; 115(36): 9002-9007, 2018 09 04.
Article in English | MEDLINE | ID: mdl-30127003

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/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1ß 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.


Subject(s)
Alzheimer Disease/metabolism , Amyloid/metabolism , Inflammasomes/metabolism , Interleukin-18/metabolism , Seizures/metabolism , Synaptic Transmission , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid/genetics , Animals , Inflammasomes/genetics , Interleukin-18/genetics , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Levetiracetam , Mice , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Piracetam/analogs & derivatives , Piracetam/pharmacology , Seizures/drug therapy , Seizures/genetics , Seizures/pathology
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