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Anti-Alzheimer's Disease Properties and Mechanisms of Alginate-Derived Unsaturated Mannuronate Oligosaccharide

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Date

2022

Authors

Supervisor

Lu, Jun
Xu, Xu

Item type

Thesis

Degree name

Doctor of Philosophy

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Publisher

Auckland University of Technology

Abstract

Alginate is a naturally acidic polysaccharide composed alternately of β-D- mannuronic acid and its C-5 epimer α-L-guluronic acid with 1,4-glycosidic linkages and widely exists in the cell walls of various brown seaweeds. Alginate and its derivatives exert a variety of biological and pharmaceutical activities. Alzheimer’s disease (AD) is the most common type of dementia in aged people with disorders clinically characterized by cognitive deficits and pathologically characterized by extracellular senile plaques mainly composed of amyloid-β (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. In ordinary life, the production and clearance of Aβ and hyperphosphorylated tau protein are in a dynamic balance. However, the failure to clear Aβ and hyperphosphorylated tau protein is regarded as an essential mechanism to exacerbate the pathological process of AD. Autophagy is a primary cellular degradation process that is responsible for the degradation and clearance of aggregated proteins and damaged organelles to maintain cellular homeostasis, depending on the fusion of autophagosomes and lysosomes. In this study, unsaturated mannuronate oligosaccharide (MOS) was obtained from alginate-derived polymannuronate via enzymatic depolymerization. The degree of polymerization of MOS ranged from mannuronate dimer to mannuronate undecamer (M2- M11), and the distribution of the molecular weight of MOS ranged from 352 Da to 1936 Da. MOS significantly inhibited the aggregation of the Aβ1-42 oligomer and Tau- K18 oligomer in vitro. In N2a-sw cells and 3×Tg-AD primary cortex neurons, MOS treatment decreased the expression of Aβ1-42 and reduced the levels of amyloid precursor protein (APP) and BACE1. Moreover, MOS significantly promoted autophagy in AD cells, which involved inactivation of the mTOR signalling pathway and facilitation of the fusion of autophagosomes and lysosomes induced by MOS. Finally, the MOS- induced decrease in APP and Aβ1-42 levels was blocked by the addition of autophagy inhibitors, confirming the involvement of autophagy in the anti-AD activity of MOS. In HEK293/Tau cells and 3×Tg-AD primary cortex neurons, MOS suppressed the levels of phosphorylated Tau protein. MOS treatment reduced the activity of glycogen synthase kinase-3β (GSK-3β) by decreasing its phosphorylation levels at the Y216 site and increasing its phosphorylation levels at the S9 site. MOS treatment increased the ratio of LC3-II/LC3-I levels and reduced the expression of p62, indicating an increase in autophagy. Finally, the MOS-induced decrease in Tau protein expression was attenuated by the addition of an autophagy inhibitor, confirming the involvement of autophagy. This is the first comprehensive investigation on the anti-Alzheimer's disease properties of MOS. The results have shed light on a novel application prospect of MOS as a promising functional food or a natural medication for the treatment or assistance of the treatment of AD.

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https://hdl.handle.net/10292/15177

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