The Study On Sulfur Nanoparticles,Composite Sulfur Nanoparticles Treated Alzheimer’s Disease By Inhibiting Of Aβ Aggregation And Reducing ER Stress

Alzheimer’s disease（AD）,a common neurodegenerative disease,is characterized by the decline of memory and cognitive ability.As the disease progresses,the AD patients lose their memory and basic self-care ability gradually and die finally in the great physical and mental pain.However,the currently AD drugs cannot effectively reduce the symptoms or prevent the progression of AD,which leads to severe economic burden for patients suffering from this disease.With the growing aging of the world population,the incidence of AD continues to rise.Therefore,the development of new types of AD therapeutic drugs is imminent.At present,the deposition of amyloid（Aβ）is considered to be a major factor in the pathogenesis of AD.Many studies have shown that neurotoxicity induced by Aβdeposition mediates several events such as synaptic loss,oxidative stress,and endoplasmic reticulum stress（ER stress）.Therefore,inhibition of the Aβdeposition may be effective in preventing and treating AD.This article is divided into the following three chapters:Chapter 1:We briefly summarized the symptoms and pathological features of AD.And then we described the main pathogenic mechanism of AD,including the formation of Aβand its toxicity.Afterwards,the current status of AD therapeutic drugs,the mechanism of blood-brain barrier,the way of the drug penetrates the blood-brain barrier,and the application prospects of nanomedicine in AD treatment are discussed in depth.Finally,we clarified the significance and purpose of this study.The second chapter:we designed and synthesized three kinds of brain-targeting sulfur nanoparticles with novel morphology（volute-like,tadpole-like and spherality-like）and respectively named as RVG@Met@VS,RVG@Met@TS and RVG@Met@SS.Here,we investigated the inhibitory effects of different sulfur nanoparticles on the aggregation of Aβand Aβ-Cu²⁺complex.Subsequently,we found that RVG@Met@SS has the best inhibitory effect due to its unique small size effect,and it can effectively protect SH-SY5Y cells from the toxicity of Aβ-Cu²⁺complex.The in vivo and in vitro experiments demonstrated that there was a significant difference between the ability of different sulfur nanoparticles to across the blood-brain barrier（BBB）.In addition,the results of Morris water maze test showed that the cognitive level of AD mice was significantly improved after RVG@Met@SS treatment.The above experimental results showed that RVG@Met@SS can be used as a potential drug for AD treatment.The third chapter:we designed and synthesized the functionalized microbubbles（Qc@SNPs-MB）with quercetin-modified sulfur nanoparticles（Qc@SNPs）.Qc@SNPs-MB can be broken instantaneously under the effect of ultrasound,and the resulting"sonoporation"can cause a transient BBB opening.At the same time,Qc@SNPs release from the broken shell and penetrate the BBB.Our results showed that this way can safely open the BBB and increase the efficiency of nanoparticles-uptake by SH-SY5Y cells.ER stress is caused by proteins misfolding and aggregation,and is considered to be associated with the pathogenesis of AD.In vitro experiments showed that Qc@SNPs could reduce the ER stress induced by thapsigargin.Moreover,Qc@SNPs reduced the apoptosis,inflammatory response,homeostasis calcium ion and oxidative stress induced by ER stress,and protected nerve cells.After Qc@SNPs treatment,the cognitive level of AD mice was significantly increased.The level of Aβin the brain and the loss of neurons were decrease.The above experimental results indicated that the drug delivery way of Qc@SNPs-MB combined with US is effective and safe.Moreover,Qc@SNPs targeting to the ER stress is a potential effective drug for the treatment of AD.