Anemarrhenae rhizoma water extract (AWE) ameliorates learning and memory impairments by activating the ADAM17/Aph-1-Notch signaling axis and restoring synaptic protein loss.

Abstract

BACKGROUND: The scopolamine (SCOP)-induced memory impairment model is a classic model for cognitive research. The Notch signaling pathway is pivotal for synaptic plasticity. OBJECTIVE: To investigate whether Anemarrhenae rhizoma water extract (AWE) ameliorates SCOP-induced synaptic dysfunction and memory impairment by activating the Notch pathway. METHODS: UPLC-Q-TOF-MS was employed technology to analyze the components of AWE. behavioral tests and HE staining were performed to evaluate cognitive function and hippocampal pathology in mice, and DIA mass spectrometry was performed for a comprehensive analysis of the hippocampal proteome analysis. Additionally, Western blotting was performed to measure the expression levels of proteins related to the Notch signaling pathway and synapses. In vitro, HT22 cells were treated with the γ-secretase inhibitor DAPT and the selective ADAM17 inhibitor TAPI-1 to verify the crucial role of the Notch pathway in mediating the protective effects of AWE. RESULTS: AWE primarily contains timosaponins BII, BIII, AI, AIII, neomangiferin, and mangiferin. Proteomic analysis revealed the upregulation of the key Notch pathway activators, ADAM17 and Aph-1, coupled with a significant overall enrichment of the Notch signaling pathway. Furthermore, AWE dose-dependently reversed SCOP-induced memory deficits, and pathological changes in the hippocampus and decreased expression of synaptic and Notch signaling proteins in mice. Critically, the protective effects of AWE on HT22 cells were completely abolished by DAPT and TAPI-1. CONCLUSIONS: AWE alleviates SCOP-induced synaptic protein loss and memory impairment by activating the Notch signaling pathway, providing new evidence for natural preventive strategies targeting Notch.