Stimulation of insulin signaling and inhibition of JNK-AP1 activation protect cells from amyloid-β-induced signaling dysregulation and inflammatory response

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DOIResolve DOI: http://doi.org/10.3233/JAD-131949
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TypeArticle
Journal titleJournal of Alzheimer's Disease
ISSN1875-8908
Volume40
Issue1
Pages105122; # of pages: 18
Subjectactin; amyloid beta protein; amyloid beta protein[1-42]; anthra[1,9 cd]pyrazol 6(2h) one; early growth response factor 2; granulocyte macrophage colony stimulating factor; insulin; interleukin 2; interleukin 23; interleukin 23p19; interleukin 32; interleukin 6; interleukin 8; macrophage inflammatory protein 1beta; monocyte chemotactic protein 1; protein c jun; stress activated protein kinase; transcription factor AP 1; transcription factor E2F1; tumor necrosis factor alpha; tumor suppressor protein; article; cell growth; cell viability; controlled study; cytokine release; cytotoxicity; densitometry; gene expression; human; human cell; immunoblotting; in vitro study; inflammation; insulin treatment; lipid oxidation; negative feedback; oxidative stress; priority journal; protein expression; protein phosphorylation; signal transduction; transcription initiation; Western blotting
AbstractOne of the hallmarks of Alzheimer's disease (AD) is the accumulation and deposition of amyloid-β (Aβ) peptides in the brain and cerebral vasculature. Aβ evokes neuroinflammation and has been implicated in insulin signaling disruption and JNK-AP1 activation, contributing to AD neuropathologies including oxidative injury and vascular insufficiencies. In this study we aim to better understand the protective mechanisms of insulin signaling and JNK-AP1 inhibition on the adverse effects of Aβ. Four-hour treatment of hCMEC/D3, the immortalized human brain endothelial cells (iHBEC), with Aβ1-42 resulted in significant c-Jun phosphorylation, oxidative stress, and cell toxicity. Concurrent treatment with Aβ1-42 and insulin or Aβ1-42 and JNK inhibitor SP600125 significantly improved cell viability. Cytokine array on conditioned media showed that insulin and SP600125 strongly reduced all Aβ 1-42-induced cytokines. ELISA confirmed the protective effect of insulin and SP600125 on Aβ-induced expression of interleukin (IL)-8 and Growth related oncogene-α (Gro-α). qRT-PCR revealed that insulin and SP600125 protected iHBEC from Aβ1-42-induced inflammatory gene expression. Transcription factor profiling showed that treatment of iHBEC with Aβ1-42, insulin, or SP600125 alone or in combination resulted in profound changes in modulating the activities of multiple transcription factors and relevant pathways, some of which were validated by western blot. Insulin treatment and JNK inhibition in vitro synergistically reduced c-Jun phosphorylation and thus JNK-AP1 signaling activation. The study suggests that activation of insulin and blocking of JNK-AP1 signaling inhibits Aβ-induced dysregulation of insulin signaling and inflammatory response.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); Human Health Therapeutics (HHT-TSH)
Peer reviewedYes
NPARC number21272247
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Record identifier57d5bd5a-b165-4aab-94e7-6b6c0dd83ed5
Record created2014-07-23
Record modified2016-05-09
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