Dauricine alleviates cognitive impairment in Alzheimer's disease mice induced by D-galactose and AlCl3 via the Ca2+/CaM pathway

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. Dysregulation of intracellular Ca²⁺ homeostasis plays a critical role in the pathological development of AD. Dauricine (DAU) is a bisbenzylisoquinoline alkaloid isolated from Menispermum dauricum DC., which can prevent the influx of extracellular Ca²⁺ and inhibit the release of Ca²⁺ from the endoplasmic reticulum. DAU has a potential for anti-AD. However, it is unclear whether DAU can exert its anti-AD effect in vivo by regulating the Ca²⁺ related signaling pathways. Here, we investigated the effect and mechanism of DAU on D-galactose and AlCl₃ combined-induced AD mice based on the Ca²⁺/CaM pathway. The results showed that DAU (1 mg/kg and 10 mg/kg for 30 days) treatment attenuated learning and memory deficits and improved the nesting ability of AD mice. The HE staining assay showed that DAU could inhibit the histopathological alterations and attenuate neuronal damage in the hippocampus and cortex of AD mice. Studies on the mechanism indicated that DAU decreased the phosphorylation of CaMKII and Tau and reduced the formation of NFTs in the hippocampus and cortex. DAU treatment also reduced the abnormally high expression of APP, BACE1, and Aβ_1-42, which inhibited the deposition of Aβ plaques. Moreover, DAU could decrease Ca²⁺ levels and inhibit elevated CaM protein expression in the hippocampus and cortex of AD mice. The molecular docking results showed that DAU may have a high affinity with CaM or BACE1. DAU has a beneficial impact on pathological changes in AD mice induced by D-galactose and AlCl₃ and may act by negative regulation of the Ca²⁺/CaM pathway and its downstream molecules such as CaMKII and BACE1.

Keywords: AlCl(3); Alzheimer's disease; Ca(2+)/CaM pathway; D-galactose; Dauricine.