Celastrol Enhances Cell Viability and Inhibits Amyloid-beta Production Induced by Lipopolysaccharide In Vitro

Background: Neuroinflammation is a notable hallmark of Alzheimer's disease pathogenesis and can markedly exacerbate amyloid pathology. Celastrol, a pentacyclic-triterpene, has been found to possess anti-inflammatory properties. Objective: The purpose of this study was to characterize the effects of celastrol on cell viability and amyloid-(A) peptide production induced by lipopolysaccharide (LPS) administration in H4 human neuroglioma cells stably transfected to overexpress human full length APP (H4-APP). Methods: H4-APP cells were exposed to 1, 10, and 100nM of celastrol in the presence of 0.1 g/ ml or 100g/ ml of LPS for 24 hours. The effects of celastrol were determined using MTT cell viability assay, immunohistochemistry, western blot, and ELISA. Results: Cell viability tests revealed that a dose-dependent death of H4-APP cells following administration of LPS. Moreover, celastrol significantly reduced (p < 0.05) cell death induced by LPS compared to LPS alone. Furthermore, the administration of celastrol was associated with a significant reduction in LPS-stimulated A production compared to LPS alone. Western blot and immunofluorescence analysis showed that exposure to celastrol increased HSP-70 and Bcl-2 expression but decreased NF.B activity, phosphorylated glycogen synthase kinase-3 (GSK-3) at tyrosine 216 and cyclooxygenase-2 (COX-2) expression, A accumulation together with a reduction of superoxide and hydrogen peroxide generation. HSP-70 siRNA abolished celastrol mediated cytoprotection. Conclusion: This study demonstrates that celastrol reduced both LPS-induced cell death and A production in vitro through increasing HSP-70 and Bcl-2 expression and reducing NF.B, COX-2, and GSK-3 expression and oxidative stress.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000339329100020&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701NeurosciencesSCI(E)PubMed4ARTICLEd.ma@imperial.ac.uk3835-8444