Protection of streptozotocin induced insulin receptor dysfunction, neuroinflammation and amyloidogenesis in astrocytes by insulin

Abstract

Impaired insulin signaling, amyloid pathology and neuroinflammation are closely associated with neurodegenerative disorder like Alzheimer's disease (AD). Our earlier studies showed that intracerebroventricular streptozotocin (STZ) induces insulin receptor (IR) signaling defect in the hippocampus, which is associated with memory impairment in rats. Astrocytes are the most abundant cells in the brain and play a major role in neuroinflammation. However, involvement of astrocytes in STZ induced IR dysfunction has not received much attention. Therefore, the present study was planned to explore the effect of STZ on IR signaling, proinflammatory markers and amyloidogenesis in rat astrocytoma cell line, (C6). STZ (100 μM) treatment in astrocytes (n = 3) for 24 h, resulted significant decrease in IR mRNA and protein expression, phosphorylation of IRS-1, Akt, GSK-3α and GSK-3β (p < 0.01). Further STZ induced amyloidogenic protein expression as evidenced by the increase in APP, BACE-1 and Aβ1-42 expression (p < 0.05) in astrocytes. STZ also significantly induced astrocytes activation as evidenced by increased expression of GFAP and p-P38 MAPK (p < 0.05). STZ treatment caused enhanced translocation of p65 NF-kB, triggered over expression of TNF-α, IL-1β, COX-2, oxidative/nitrosative stress and caspase activation (p < 0.05) in astrocytes. Insulin (25–100 nM) pretreatment (n = 3) significantly prevented changes in IR signaling, amyloidogenic protein expression and levels of proinflammatory markers (p < 0.05) in STZ treated astroglial cells. In the present study, the protective effect of insulin suggests that, IR dysfunction along with amyloidogenesis and neuroinflammation may have played a major role in STZ induced toxicity in astrocytes which are relevant to AD pathology.