Regulatory Effect And Mechanism Of Tannin On The Phosphorylation Of Tau Protein In The Brain Of Dementia Rats Induced By Intracerebroventricular Injection Of Streptozotocin

ObjectivesXanthoceraside, a novel triterpenoid saponin extracted from the fruit husks of Xanthoceras sorbifolia Bunge, can reverse cognitive deficits in several Alzheimer’s disease (AD) animal models. However, whether xanthoceraside has a positive effect on hyperphosphorylated tau protein remains unclear. Increasing evidence suggests the involvement of the insulin signaling pathway in neurodegenerative disorders such as AD. Thus, we used an AD animal model of cognitive impairment induced by the intracerebroventricular (icv) injection of streptozotocin (STZ) to test the effects of xanthoceraside on behavioral impairments and other mechanisms.Materials and methodsSTZ (3 mg/kg) was injected icv twice at an interval of 48 h to produce memory impairment. The rats were administered with xanthoceraside (0.06,0.12 or 0.24 mg/kg), memantine (2 mg/kg), donepezil (1 mg/kg) or vehicle from the day of the second STZ injection. The Y-maze test, novel object recognition test and Morris water maze test were performed 21,22 and 26 d after the second STZ injection, respectively. IR, IGF-1R, IGF-1, phosphatidylinositol-3-kinase (PI3K)/serine/threonine protein kinase B (Akt), Raf-1/ERK/CREB, hyperphosphorylated tau, glycogen synthase kinase-3p (GSK-3β), Cdk2, protein phosphatase 1 (PP-1), protein phosphatase 2A (PP-2A) and O-G1cNAc were also tested by Western blot or Immunofluorescence staining.ResultsWe observed that xanthoceraside treatment significantly rescued STZ-induced learning and memory impairment, as well as IR, IGF-1R and IGF-1 expression levels. STZ inhibited the PI3K/Akt and Ras/ERK signaling cascades and decreased the phosphorylation of CREB; these effects were attenuated by xanthoceraside treatment. Xanthoceraside treatment significantly lowered the level of STZ-induced hyperphosphorylated tau protein, decreased GSK-3P (tyr216) phosphorylation and enhanced PP-2A and PP-1 expressions. Xanthoceraside also increased the level of protein O-GlcNAc expressions.ConclusionsXanthoceraside is effective in providing protection against learning and memory deficits and inhibiting tau hyperphosphorylation. The possible mechanism is through the protection of insulin signaling, the inhibition of the PI3K/Akt-dependent GSK-3β signaling pathway and an enhancement of phosphatases activity. Xanthoceraside increased protein O-GlcNAc which may contribute to the inhibition of tau hyperphosphorylation.