Neuroprotective Effects Of Chitosan Oligosaccharides On Alzheimer’s Disease And Its Related Mechanisms

Alzheimer’s disease(AD)is a chronic neurodegenerative disease characterized by cognitive deficits and memory disorders.However,after decades of research,there still have been no efficacious therapies for the treatment of AD.Current treatment for AD is only symptomatic and cannot prevent or reverse the disease progression.Thus,the development of drugs with the potential to change the progression of the disease has been a priority.Due to its complex molecular mechanism,traditional treatment strategies have modest benefit.In recent years,the therapeutic strategy for AD has changed gradually from one single to a holistic treatment.Compared with one single therapeutic strategy,the holistic treatment has a lot of advantages.Natural products and their derivatives have attracted much attention due to their high bioavailability,low toxicity and multi-functional properties.Therefore,it might be an effective and feasible approach to use natural products with good biological activity for AD treatment.COS,oligosaccharides of chitosan,have received considerable attention as functional,renewable,nontoxic,and biodegradable natural ones for diverse applications,especially in pharmaceutics.Recently,multiple lines of evidences have suggested that COS possess good neuroprotective properties.This study was designed to explore the effects of COS on AD progression and try to detect its related mechanism via in vitro and in vivo studies.Here,the works mainly included the following issue.1.It has been proved that COS possess good neuroprotective properties.However,these studies were mainly verified by in vitro cellular models,and whether COS can reach the brain to exert their neuroprotective effects directly remains elusive.Blood-brain barrier(BBB)is an impediment for the delivery of therapeutic agents to the brain.In this study,to determine the permeation ability of COS across the BBB in vitro,a single layer of brain microvascular bEnd.3 cells as a BBB model in vitro was used.The results indicated that COS showed good BBB penetration ability.And Glucose transporter1(GLUT1)was one of the transporters accounting for COS penetration of the BBB.The conclusion was further confirmed by the results of biodistribution of COS in mice through detecting the fluorescence intensity of Cy7-labeled COS using an in vivo imaging system.2.It is proven that β-amyloid(Aβ)aggregates containing cross-β-sheet structures led to oxidative stress,neuroinflammation,and neuronal loss via multiple pathways.Therefore,reduction of Aβ neurotoxicity via inhibiting aggregation of Aβ or dissociating toxic Aβ aggregates into nontoxic forms might be effective therapeutic methods for AD treatment.The experimental results showed that COS efficiently interfered with Aβ42 aggregation in dose-,degree of deacetylation(DDA)and degree of polymerization(DP)-dependent manners.As a result,COS significantly ameliorated Aβ42-induced cytotoxicity,oxidative stress and inflammatory cytokines release.In the study,it was confirmed that COS could directly bind with Aβ42 oligomers directly via electrostatic and hydrophobic interaction,transformed β-sheet structures to β-turn and coil structure.The changes will disrupt the intramolecular interaction and disassembly the performed aggregates.Furthermore,interaction with COS decrease the binding probability with other Aβ42 oligomers,which leads to a failure extension of Aβ42 aggregates in the normal direction.Moreover,the DP-and DDA dependent manner was,to some extent,attributable to their different binding affinities towards Aβ42.The numbers of exposed amino and hydroxyl groups of COS played a vital role during the interaction.3.It is proven that AD is closely related to gut microbial alteration.Due to this,the modification of gut microbiota as a therapeutic strategy in AD has gained the attention of the researchers in recent years.Normally,the dysbiosis of gut microbiota can be reconditioned by prebiotics in laboratory experiments or clinical applications.This part was designed to explore the effects of COS on cognitive deficits of mice induced by Aβ42 oligomers-injection.Here,COS treatment significantly alleviated cognitive impairment,accompanied by the suppression of chronic inflammation and intestinal barrier damage.In addition,gut microbiota perturbation was observed in AD mice model,whereas COS administration dramatically reshaped the dysbiosis of intestinal bacteria,which partly led to homeostasis of metabolic pathways of gut microbiota.For the first time it was demonstrated that COS ameliorated cognitive impairment and neuroinflammation in AD model mice by reshaping the structure of intestinal bacteria.Therefore,the modification of gut microbiota by COS would represent a promising therapeutic strategy for the treatment of AD in future.Furthermore,we used pseudo-germfree mice and fecal microbiota transplantation(FMT)to confirm that COS ameliorated AD related pathological symptoms via multiple pathways in a holistic approach.Taken together,our studies would point towards a potential role of COS in treatment of AD.