Journal Article

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

DePaula Tamburro, Nelsy, Germain, Gail, Thatcher, Elizabeth Jeanne, Okabe, Shigeo, Mao, Wenjie, Hasegawa, Yuto, Futai, Kensuke, Cheung, Amy, Tzeng, Te-Chen, Golenbock, Douglas T., Caffrey, Daniel R., Heneka, Michael T., Iguchi, Risa, Latz, Eicke

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Alzheimer Disease - drug therapy / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid - genetics / Amyloid - metabolism / Amyloid precursor protein / Animals / Anticonvulsants / Biological Sciences / Convulsions & seizures / Cytokines / Etiracetam / Gene expression / Immunology and Inflammation / Inflammasomes / Inflammasomes - genetics / Inflammasomes - metabolism / Interleukin 1 / Interleukin 18 / Interleukin-18 - genetics / Interleukin-18 - metabolism / 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 / Organic chemistry / Pathogenesis / Piracetam - analogs & derivatives / Piracetam - pharmacology / Presenilin 1 / Proteins / Seizing / Seizures / Seizures - drug therapy / Seizures - genetics / Seizures - metabolism / Seizures - pathology / Spine / Synaptic density / Synaptic Transmission / β-Amyloid