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Alzheimer's disease (AD) is an enervating and chronic progressive neurodegenerative disorder, occurring frequently in the elderly and adversely affecting intellectual capabilities and the cognitive processes. Bergenin possesses efficacious antioxidant, antiulcerogenic, anti-HIV, hepatoprotective, neuroprotective, anti-inflammatory and immunomodulatory activity along with antinociceptive effect and wound healing properties. Previous studies have shown that bergenin has in vitro bovine adrenal tyrosine hydroxylase inhibitory activity, mushroom tyrosinase inhibitory activities, β-secretase (BACE-1) enzyme inhibitory activity and prevented neuronal death in the primary culture of rat cortical neurons. Protein tyrosine phosphatase-1B (PTP1B) is an intriguing target for anticancer and antidiabetic drugs and has recently been implicated to act as a positive regulator of neuroinflammation. Bergenin is also found to inhibit human protein tyrosine phosphatase-1B (hPTP1B) in vitro. Thus, bergenin was screened by molecular docking study using GOLD suite (version 5.2), CCDC for predicting its activity against targets of AD management like acetylcholinesterase (AChE) (1B41), butyrylcholinesterase (BuChE) (1P0I), Tau protein kinase 1 (GSK-3β) (1J1B), BACE-1 (1FKN) wherein the GOLD score and fitness of bergenin were comparable to those of standard drugs like donepezil, galanthamine, physostigmine, etc. Bergenin demonstrated dose-dependent inhibition of both AChE and BuChE in vitro and found to be safe up to 50 μM when screened in vitro on SH-SY5Y cell lines by cytotoxicity studies using MTT and Alamar blue assays. It also led to dose-dependent prevention of NMDA induced toxicity in these cells. Pretreatment with bergenin (14 days) in rats at three dose levels (20, 40 and 80 mg/kg; p.o.) significantly (p < 0.01) and dose-dependently alleviated amnesia induced by scopolamine (2 mg/kg, i.p.). The therapeutic effect of bergenin supplementation for 28 days, at three dose levels, was also evaluated in streptozotocin (3 mg/kg, ICV, unilateral) induced AD model in Wistar rats using Morris water maze and Y maze on 7th, 14th, 21st and 28th days. STZ caused significant (p < 0.001) cognitive impairment and cholinergic deficit and increased oxidative stress in rats. Bergenin could significantly ameliorate STZ induced behavioral deficits, inhibit the AChE and BuChE activity in parallel with an increase in the diminished GSH levels in a dose-dependent fashion. The histopathological investigations were also supportive of this datum. The bergenin treatment at 80 mg/kg led to significant (p < 0.05) abatement of the raised Aβ-1-42 levels and alleviated the perturbed p- tau levels leading to significantly low (p < 0.01) levels of p-tau in brain homogenates of rats as compared to ICV STZ injected rats. In conclusion, the observed effects might be attributed to the cholinesterase inhibitory activity of bergenin coupled with its antioxidant effect, anti-inflammatory activity and reduction of Aβ-1-42 and p-tau levels which could have collectively helped in the attenuation of cognitive deficits. The current findings of the study are indicative of the promising preventive and ameliorative potential of bergenin in the management of AD through multiple targets.Docking of bergenin into AChE, BuChE, BACE-1 and tau protein kinase- I (GSK-3β) showed high GOLD fitness and internal GOLD scores.Bergenin was safe up to 50 μM in MTT and Resazurin reduction-based assay and prevented NMDA induced cytotoxicity in SH-SY5Y cells.It reduced MEL in MWM and MPA in Y maze when evaluated in scopolamine induced amnesia and ICV STZ induced model of AD in rats.It inhibited AChE and BuChE, attenuated oxidative stress through increased GSH levels and caused restoration of hippocampal cytoarchitecture.ELISA assays showed a significant reduction in Aβ1-42 levels and phosphorylated tau protein levels in brain homogenates of rats.