Functionalized Nano Ruthenium And Nano Palladium For The Treatment Of Alzheimer's Disease By Inhibiting Tau Protein Hyperphosphorylation And Reducing Oxidative Stress

Alzheimer's disease(AD)is the most common neurodegenerative disease.AD patients present with progressive cognitive impairment,learning and memory abilities decline,and eventually self-care ability is lost until death.According to statistics,by 2050,1 in 85 people worldwide will have AD,which will cause a huge burden on families and society.Therefore,it is of great significance to prevent AD and treat AD patients suffering from memory loss and behavioral disorders.For the study of AD drugs,amyloid-?(A?)is the main target.However,to date,all candidate drugs that only target A? have not been successful.At this point,researchers are turning to other targets or multi-target drugs for AD.Some studies have shown that tau's pathology,oxidative stress,mitochondrial dysfunction,and neuroinflammation are several key pathogenic factors in the development of AD,and they are interrelated and interact.Therefore,it is essential to develop AD drugs that target multiple targets such as Tau and oxidative stress.This article is divided into the following three chapters:Chapter 1: First,the related pathological mechanisms of AD are introduced,including Tau protein pathology,oxidative stress,and neuroinflammation.The structure and function of the blood-brain barrier(BBB)were then summarized,and the method of drug passing through BBB were discussed.The current AD treatment methods and the research progress of nanotechnology in the treatment of AD were reviewed.Finally,the significance and purpose of this research's topic selection are explained.Chapter 2: Inhibition of hyperphosphorylation of tau protein and reduction of neuronal damage have become promising methods for the treatment of AD.We herein designed a novel nanocomposite(NGF-PCM@Ru NPs)with high stability and good biocompatibility by using flower-shaped hollow nano-ruthenium(Ru NPs)as a carrier,loading nerve growth factor(NGF)and sealing with phase change material(PCM).Due to its excellent photothermal effect,under the near-infrared(NIR)irradiation,the nanocomposite could effectively penetrate the blood-brain barrier(BBB)and respond to phase changes in the lesion area,releasing NGF,which inhibited tau hyperphosphorylation,reduced oxidative stress,and more importantly restored nerve damage and maintained neuronal morphology,thereby significantly improving learningand memory in AD mice.Thus,the experimental results indicate that multifunctional nanocomposites may be a promising drug in the treatment of AD.Chapter 3: Oxidative stress-induced mitochondrial dysfunction plays a key role in the pathogenesis of AD.Mitochondrial dysfunction induces abnormal production of reactive oxygen species(ROS),leading to nerve cell death.The octahedral Pd nanozymes(Pd NPs)have antioxidant enzyme-like activity and can effectively remove ROS.However,due to its low blood-brain barrier(BBB)permeability,it cannot target in the brain of AD and effectively accumulate.Here,we designed an octahedral palladium nanoenzyme system(Pd@PEG@Bor)modified by Borne(Bor).In cell experiments,the results showed that Bor could promote the uptake of Pd@PEG@Bor by SH-SY5 Y cells.In addition,Pd@PEG@Bor could effectively remove excessive ROS in SH-SY5 Y cells,and reduce mitochondrial function damage and apoptosis caused by oxidative stress.In the AD model mouse experiment,Pd@PEG@Bor was able to rapidly and continuously accumulate in the brain of AD mice under the action of Bor.More importantly,after AD mice were treated with Pd@PEG@Bor,their learning ability and memory function were significantly improved;A? deposition,neuron loss,and inflammatory reactions in AD brains were significantly reduced.In summary,the experimental results indicate that Pd@PEG@Bor nanozymes have potential application value by removing ROS to block AD progression.