To understand the role of IL18 in the development of concomitant seizure disorders in Alzheimer’s disease (AD)

The connection between neuroinflammation and the progressive loss of neurons in AD is well known; however, the fact that most patients with AD suffer from seizures is underappreciated. The NLRP3 inflammasome, a major source of the pro-inflammatory cytokines IL1β and IL18, drives the pathology of AD in APP/PS1 mice. We previously reported that NLRP3 inflammasome knockout (KO) mice, when bred into APP/PS1 mice, are completely protected from amyloid induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. Here, we investigate the impact of IL18 deficiency in APP/PS1 mice.

IL18 KO mice were bred with APP/PS1 mice (IL18KO/APP/PS1). IL18KO/APP/PS1 and control group mice were monitored for survival over 10 months. IL18-deficient mice were chemically induced with seizures and treated with the anticonvulsant drug levetiracetam to evaluate changes in survival rate. Gene and protein expression related to the regulation of neuronal excitability was analyzed with quantitative PCR and immunoblot, respectively. Dendritic spine morphology in hippocampal CA1 pyramidal neurons was visualized using a lipophilic tracer (DiO). Field excitatory postsynaptic potentials in hippocampal CA1 synapses were measured.

Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by 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.

IL18-deficient APP/PS1 mice were unpredictably rendered hypersusceptible to fatal grand mal seizures. This is surprising given IL18’s numerous pro-inflammatory effects. Here, this study identifies a novel role for IL18 in suppressing aberrant neuronal transmission in AD.