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 (1â¯mg/kg and 10â¯mg/kg for 30â¯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 Aß1-42, which inhibited the deposition of Aß 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.
Subject(s)
Alzheimer Disease , Benzylisoquinolines , Cognitive Dysfunction , Neurodegenerative Diseases , Mice , Animals , Alzheimer Disease/chemically induced , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Galactose/toxicity , Galactose/metabolism , Amyloid Precursor Protein Secretases/adverse effects , Amyloid Precursor Protein Secretases/metabolism , Neurodegenerative Diseases/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Molecular Docking Simulation , Aspartic Acid Endopeptidases/adverse effects , Aspartic Acid Endopeptidases/metabolism , Benzylisoquinolines/adverse effects , Hippocampus , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Disease Models, Animal , Amyloid beta-Peptides/metabolism , Mice, TransgenicABSTRACT
The seed embryo of Nelumbo nucifera Gaertn. is a famous traditional Chinese medicine and food which is considered conducive to the prevention of Alzheimer's disease (AD). In this study, the effect and mechanism of TASENN (total alkaloids from the seed embryo of Nelumbo nucifera Gaertn.) on AD mice and amyloid-ß (Aß) injured PC12 cells were evaluated. HPLC-UV analysis showed that the extracted TASENN (purity = 95.6%) mainly contains Liensinine, Isoliensinine, and Neferine (purity was 23.01, 28.02, and 44.57%, respectively). In vivo, oral treatment with TASENN (50 mg/kg/day for 28 days) improved the learning and memory functions of APP/PS1 transgenic mice, ameliorated the histopathological changes of cortical and hippocampal neurons, and inhibited neuronal apoptosis. We found that TASENN reduced the phosphorylation of Tau and the formation of neurofibrillary tangles (NFTs) in APP/PS1 mouse brain. Moreover, TASENN down-regulated the expression of APP and BACE1, ameliorated Aß deposition, and inhibited microglial proliferation and aggregation. The elevated protein expression of CaM and p-CaMKII in APP/PS1 mouse brain was also reduced by TASENN. In vitro, TASENN inhibited the apoptosis of PC12 cells injured by Aß25-35 and increased the cell viability. Aß25-35-induced increase of cytosolic free Ca2+ level and high expression of CaM, p-CaMKII, and p-Tau were decreased by TASENN. Our findings indicate that TASENN has a potential therapeutic effect on AD mice and a protective effect on PC12 cells. The anti-AD activity of TASENN may be closely related to its negative regulation of the CaM pathway.
Subject(s)
Alkaloids , Alzheimer Disease , Cognitive Dysfunction , Nelumbo , Mice , Animals , Rats , Nelumbo/metabolism , Amyloid Precursor Protein Secretases/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/therapeutic use , PC12 Cells , Aspartic Acid Endopeptidases/therapeutic use , Amyloid beta-Peptides/metabolism , Alzheimer Disease/metabolism , Mice, Transgenic , Alkaloids/therapeutic use , Disease Models, Animal , Amyloid beta-Protein Precursor/geneticsABSTRACT
Excessive accumulation of amyloid-ß (Aß) is the leading cause of Alzheimer's disease (AD). Liensinine, Isoliensinine, and Neferine are main alkaloids in lotus seed embryos. In this paper, the protective effects of Liensinine, Isoliensinine, and Neferine on Aß25-35 -injured PC12 cells were studied. It was found that Liensinine, Isoliensinine, and Neferine could improve the viability and reduce the apoptosis of PC12 cell induced by Aß25-35 . These three alkaloids could also reduce the level of intracellular free Ca2+ and CaM expression in Aß25-35 -treated cells, thereby inhibiting the phosphorylation of CaMKII and tau. In addition, these three compounds can inhibit the production of ROS in PC12 cells injured by Aß25-35 . Our results suggest for the first time that Liensinine, Isoliensinine, and Neferine can inhibit hyperphosphorylation of tau protein by inhibiting the Ca2+ -CaM/CaMKII pathway, thereby reducing the apoptosis and death of PC12 cells damaged by Aß25-35 . PRACTICAL APPLICATIONS: This study highlighted the protective effects and mechanisms of three main active ingredients (Liensinine, Isoliensinine, and Neferine) in the lotus embryo on a typical cell model of Alzheimer's disease (AD). The results revealed that three alkaloids in this healthy food might exert therapeutic potential for AD.
