Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells

Abstract

BackgroundAlzheimer’s disease (AD) involves increased accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles as well as neuronal loss in various regions of the neocortex. Neuroinflammation is also present, but its role in AD is not fully understood. We previously showed increased levels of pro-inflammatory cytokine interleukin-18 (IL-18) in different regions of AD brains, where it co-localized with Aβ-plaques, as well as the ability of IL-18 to increase expression of glycogen synthase kinase-3β (GSK-3β) and cyclin dependent kinase 5, involved in hyperphosphorylation of tau-protein. Elevated IL-18 has been detected in several risk conditions for AD, including obesity, type-II diabetes, and cardiovascular diseases as well as in stress.MethodsWe differentiated SH-SY5Y neuroblastoma cells as neuron-like and exposed them to IL-18 for various times. We examined the protein levels of amyloid-β precursor protein (APP) and its processing products, its cleaving enzymes, involved in amyloidogenic processing of APP, and markers of apoptosis.ResultsIL-18 increased protein levels of the β-site APP-cleaving enzyme BACE-1, the N-terminal fragment of presenilin-1 and slightly presenilin enhancer 2, both of which are members of the γ-secretase complex, as well as Fe65, which is a binding protein of the C-terminus of APP and one regulator for GSK-3β. IL-18 also increased APP expression and phosphorylation, which preceded increased BACE-1 levels. Further, IL-18 altered APP processing, increasing Aβ40 production in particular, which was inhibited by IL-18 binding protein. Increased levels of soluble APPβ were detected in culture medium after the IL-18 exposure. IL-18 also increased anti-apoptotic bcl-xL levels, which likely counteracted the minor increase of the pro-apoptotic caspase-3. Lactate dehydrogenase activity in culture medium was unaffected.ConclusionsThe IL-18 induction of BACE-1, APP processing, and Aβ is likely to be linked to stress-associated adaptations in neurons during the course of normal functioning and development. However, in the course of wider changes in the aging brain, and particularly in AD, the effects of heightened or prolonged levels of IL-18 may contribute to the process of AD, including via increased Aβ.

The TLR and IL-1 signalling network at a glance

“…IRAK1 inhibitors could therefore have therapeutic potential for the treatment of autoimmune diseases that are linked to the overproduction of type 1 IFNs by pDCs (Barrat et al, 2005). They might also reduce IL-18 secretion by inflammasomes, and so reduce IL-18-stimulated production of type II interferon (IFNc) by T cells, which is associated with severe inflammatory reactions, and autoimmune and other diseases Sutinen et al, 2012). In mouse and human macrophages, IRAK2 is required for the TLR-dependent production of proinflammatory cytokines (Flannery et al, 2011;Pauls et al, 2013).…”

Pomegranate inhibits neuroinflammation and amyloidogenesis in IL-1β-stimulated SK-N-SH cells

“…These have been supported 23 by reports demonstrating that Aβ peptides could activate NF-κB in neurons [10]. 24 NFκB pathway therefore provides an important target in the understanding of 25 mechanisms involved in modulating inflammation in the neurons. 26 Accumulation of extracellular Aβ plaques in neurons is one of the important 27 pathological hallmarks in AD.…”

Features of molecule expression markers of insulin resistance in experimental Alzheimer’s disease

“…In vivo показано, что вос-паление сопровождается образованием и накопле-нием β-амилоида [21]. β-Амилоид активирует ми-кроглию и астроциты, которые в свою очередь запу-скают процесс высвобождения провоспалительных цитокинов, ингибирующих рецепторы инсулина за счет увеличения форфорилирования серина IRS-1 (insulin substrate-1) и протеинкиназы В (Akt-киназы), что способствует развитию нейродегенера-ции [28].…”

“…В ольфакторной луковице наблюдалась тенденция к повышению экспрессии IL-18 у крыс с моделированной нейродегенерацией. Это может свидетельствовать об активации воспалительного процесса за счет сборки внутриклеточных инфлам-масом [21].…”