Bushen-Huatan-Yizhi formula reduces spatial learning and memory challenges through inhibition of the GSK-3β/CREB pathway in AD-like model rats

Abstract

Background: There is an increase in cases of Alzheimer's disease (AD) stemming from a globally ageing population demographic. Although substantial research efforts were performed for the scope of prophylaxis and therapeutic measure development against AD, based on its pathogenesis, most were unsuccessful. Bushen-Huatan-Yizhi formula (BSHTYZ) is extensively implemented to manage dementia. However, few studies have been carried out to understand how BSHTYZ enhances recovery of spatial learning and memory and how it modulates relevant molecular interplays in order to achieve this.

Purpose: To investigate neuroprotective function, ameliorating learning/memory capacity of BSHTYZ via GSK-3β / CREB signaling pathway in rat AD models influenced through Aβ_1-42.

Methods: A total of 60 male SD rats (3 months old) were randomized into six groups and treated with 2.6 μg/μl Aβ_1-42 (5 μl) into the lateral ventricle, though the control group (Con) was administered an equivalent volume of vehicle. Consequently, the rat cohorts were administered either BSHTYZ or donepezil hydrochloride or normal saline, by intragastric administration, for four weeks. Spatial learning / memory were detected through the Morris water maze, and possible mechanisms detected by histomorphological examination and Western blot in the rat AD models induced by Aβ_1-42.

Results: Spatial learning/memory issues were monitored after Aβ_1-42 infusion in rats. Simultaneously, neuron loss in cornuammonis1 (CA1) / dentate gyrus (DG) within hippocampus region were identified, together with enhanced black granule staining within the hippocampus and hyperphosphorylated tau within Ser202 and Ser396 sites. It was also elucidated that Aβ_1-42 had the capacity to up-regulate glycogen synthase kinase-3β (GSK-3β) and down-regulate cAMP response element binding protein (CREB). BSHTYZ was found to reverse such molecular interplays.

Conclusion: The study suggested BSHTYZ could possibly provide neuroprotective role against learning / memory impairment, which provided a potential therapeutic tool delaying the progression of AD molecular interplays that includes the GSK-3β / CREB signaling pathway.

Keywords: Alzheimer's disease; BuShen-HuaTan-YiZhi formula; Glycogen synthase kinase-3β; Hyperphosphorylated tau protein; Spatial learning and memory deficits; cAMP response element binding protein.