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

Journal of Neuroinflammation

Johanna O Ojala³  Antero Salminen¹  George Anderson²  Elina M Sutinen³ 

[1] Kuopio University Hospital, Neurology, P.O.B. 1777, FI-70211, Kuopio, Finland;CRC, Rm30, 57 Laurel Street, Glasgow, Scotland, UK;University of Eastern Finland, Clinical Research Centre/ Brain Research Unit, Mediteknia, P.O.B. 1627, FI-70211, Kuopio, Finland

关键词: Presenilin;    BACE;    Alzheimer’s disease;    Amyloid-beta;    Inflammation;    Interleukin-18;   

Others  :  1160293
DOI  :  10.1186/1742-2094-9-199

 received in 2012-03-09, accepted in 2012-07-28,  发布年份 2012

【 摘 要 】

Background

Alzheimer’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.

Methods

We 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.

Results

IL-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.

Conclusions

The 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.

【 授权许可】

   
2012 Sutinen et al.; licensee BioMed Central Ltd.

【 图 表 】

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