The Isoquinoline Alkaloid Dauricine Targets Multiple Molecular Pathways to Ameliorate Alzheimer‐Like Pathological Changes In Vitro

Abstract

Alzheimer's disease (AD), the most common neurodegenerative disease, has no effective treatment. Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, reportedly has neuroprotective effects in cerebral ischemia. Here, we investigated the effects of DAU on N2a cells stably transfected with Swedish mutant amyloid precursor protein (N2a/APP), an AD-like cell model. ELISA and Western blot analysis revealed that DAU inhibited APP processing and reduced Aβ accumulation. In addition, DAU ameliorated tau hyperphosphorylation via PP2A, p35/25, and CDK5 pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by DAU was also validated in HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis revealed 85 differentially expressed proteins in the lysates between the wild-type N2a cells (N2a/WT) and the N2a/APP cells in the presence or absence of DAU; these were classified into 6 main categories according to their functions: endoplasmic reticulum (ER) stress-associated proteins, oxidative stress-associated proteins, cytoskeleton proteins, molecular chaperones, mitochondrial respiration and metabolism-related proteins, and signaling proteins. Taken together, we demonstrated that DAU treatment reduces AD-like pathology, thereby suggesting that DAU has potential therapeutic utility in AD.

Dauricine Attenuates Spatial Memory Impairment and Alzheimer-Like Pathologies by Enhancing Mitochondrial Function in a Mouse Model of Alzheimer's Disease

“…Moreover, Western blot analysis showed that DAU treatment could reduce phosphorylated tau at the dose of 1 mg/kg/d. Pathological changes of Aβ and tau proteins are consistent with the findings of our previous in vitro study (Liu et al, 2018 ). In the in vitro study, DAU treatment inhibited APP processing to reduce Aβ production and attenuated tau pathology through PP2A and p35/25, and the main mechanism may have involved antioxidant stress.…”

“…In addition, DAU can ameliorate tau hyperphosphorylation (Wang et al, 2005 ) and promote β-amyloid (Aβ) 1−42 clearance by releasing bradykinin (Pu et al, 2018 ). Our group has previously confirmed the neuroprotective effect of DAU on AD model cells (Liu et al, 2018 ). However, its beneficial effects and the underling mechanisms in vivo are unknown and require further investigation in AD animal models.…”

“…DAU, a bisbenzylisoquinoline alkaloid, is isolated from dauricum DC, and can treat various diseases such as cardiac ischemia, angina, and inflammation, as well as inhibit angiogenesis in tumors and promote apoptosis in tumor cells (Xia et al, 2002 ; Tang et al, 2009 ; Yang et al, 2010 ). Our previous study showed that DAU treatment attenuated hyperphosphorylation of tau and production of Aβ in N2a/APP cells (Liu et al, 2018 ). In this study, we further confirmed that DAU can improve cognitive impairment and neurodegeneration in 3xTg-AD mice.…”

Network Pharmacology-Based Analysis of Xiao-Xu-Ming Decoction on the Treatment of Alzheimer’s Disease

“…Dauricine is a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC., and it has been found to have significant neuroprotective effect on AD. Dauricine has the pharmacological activity of inhibiting APP processing, reducing Aβ accumulation, attenuating the hyperphosphorylation of tau ( Liu et al, 2018 ), anti-oxidative and anti-apoptosis, and shows the potential therapeutic value for AD ( Wang et al, 2020 ).…”

Recent Progress on Biological Activity of Amaryllidaceae and Further Isoquinoline Alkaloids in Connection with Alzheimer’s Disease

“…Dauricine, a bisbenzylisoquinoline alkaloid isolated from the rootstock of Menispermum dauricum (Menispermaceae) [124], has been studied for its neuroprotective effects in a murine neuroblastoma cell line (N2a) stably transfected with the human Swedish mutant form of amyloid protein precursor (APP), an AD-like cell model [125]. Employing this cell model, which overexpresses APP and hyperphosphorylates tau protein [126], and ELISA and Western blot analysis, it has been revealed that dauricine inhibited APP processing and reduced Aβ accumulation [125].…”