Alzheimer's and seizures: interleukin-18, indoleamine 2,3-dioxygenase and quinolinic Acid

Abstract

Emergent seizures are common in Alzheimer's disease (AD), although the mechanisms mediating this are unknown. It is proposed that stress induced interleukin-18 (IL-18), via interferon-gamma (IFNy) and independently, increases indoleamine 2,3-dioxygenase (IDO) and subsequent quinolinic acid (QA) in microglia. QA increases seizures and concurrently contributes to neuronal loss via excitotoxicity. The ApoE4 allele interacts with IL-18 polymorphisms to increase the risk of AD, and seems likely to potentiate the emergence of seizures. Concurrent changes in IDO and the kynurenine pathways at the blood-brain-barrier (BBB) have implications for treatment, including in the efficacy of different anti-hypertensives. Melatonin is proposed to inhibit these overlapping excitotoxic and neurodegenerative processes, and would be a useful adjunctive treatment.

Keywords: Alzheimer’s; IDO; IL-18; astrocytes; losartan; melatonin; microglia; seizures.

Summary Figure.

Showing the proposed pathways whereby stress and IL-18 polymorphisms mediate an increase in IL-18, with impacts concurrently on seizures neuroexcitotoxicity and neurodegeneration. Infection effects on RAGE activity and LRP-1 levels will lead to an increase in AB in the brain. Via the inhibition of the VEGFr2, then AB will inhibit the efficacy of Losartan/EXP3179, with concurrent changes in permeability. In microglia AB will lead to a decrease in the reactivity threshold, likely involving S1Pr activation, within the context of wider rearranged lipid raft complexes. AB will lower the threshold for IFNy induced IDO, perhaps in part via autocrine TNFa, leading to an increase in QA. IL-18 will be induced in both glia and neurons, via ROS induced inflammasome and Caspase-1 induction. Decreases in Dopamine, NE, and Ach will contribute to cognitive difficulties. The decrease in D and NE, via the loss of cAMP induction, may contribute to a decrease in astrocyte KA production. Such increases in IDO will drive tryptophan down the kynurenine pathway, leading to a decrease in the levels of serotonin and melatonin, further exacerbating mood and oxidant status. ApoE4 interacts with IL-18 polymorphisms in mediating an increase in sporadic Alzheimer’s, and this interaction may increase the likelihood of concurrent seizures, either directly and/or indirectly via an increase in QA. Melatonin will have multiple sites of action, via changes in oxidant status in all cell types. Amyloid B and IL-18 effects are not shown in astrocytes for clarity. Abbreviations: a7nAChr, alpha 7 nicotinic acetylcholine receptor; AB, amyloid B; ACh, acetylcholine; BBB, blood brain barrier; D, dopamine; GSK-3b, glycogen synthase kinase-3beta; IDO, indoleamine 2,3-dioxygenase; IFNy, interferon-gamma; IL-18, interleukin 18; IL-1b, interleukin-1beta; KA, kynurenic acid; KAT, kynurenine aminotransferase; Kyn, kynurenine; LRP-1, low density lipoprotein receptor-related protein-1; PHOX, phagocyte oxidase; P-tau, tau hyperphosphorylation; NE, norepinephrine; NMDAr, N-methyl-D-aspartate receptor; nSM, neutral SphingoMyelinase; QA, quinolinic acid; RAGE, receptor for glycation end-products; ROS, reactive oxidant status; S1P1r, sphingosine-1-phosphate receptor-1; VEGFr2, vascular endothelial growth factor receptor 2.