The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophagy in Aβ clearance. Recent studies implied that extracts from Semiaquilegia adoxoides (DC.) Makino could ameliorate the memory of D-galactose induced aging mice. However, the bioactive substance and underlying mechanism remains unknown. Thus, the present study sought to explore the effects of a novel homogenous peptidoglycane on Aβ 42 secretion and the underlying mechanism. Briefly, we extracted a novel peptidoglycan named SA02C using hot water extraction and alcohol precipitation with the Mw of 13.72 kDa. SA02C contains 73.33% carbohydrate and 27.83% protein. The structure characterization revealed that its glycan part might mainly composed of galacturonic acid with minor rhamnose in backbone, and branched with glucose, galactose, arabinose, xylose and galacturonic acid. The protein or peptide moiety in SA02C was bonded to the polysaccharide via threonine. Bioactivities test showed that SA02C could reduce Aβ 42 production in a dose dependent manner with no obvious cytotoxicity. Mechanism study demonstrated that SA02C could modulate APP processing by upregulating the expression of ADAM10, sAPPα and downregulating BACE1, sAPPβ. Furthermore, SA02C also could stimulate autophagy by promoting the expression of the markers of autophagy such as LC3B and ATG5, resulting in the promotion of Aβ 42 phagocytosis.
Pan Liu,Xiao Chen,Haizhe Zhou,Liqun Wang,Zaijun Zhang,Xiaohu Ren,Feiqi Zhu,Yi Guo,Xinfeng Huang,Jianjun Liu,Peter S. Spencer,Xifei Yang
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.
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