Polydopamine-mediated Nanosystems Modulates The Circulation Between Aβ And Neuroinflammation In Alzheimer’s Disease

Alzheimer’s disease(AD)is the most common neurodegenerative disease in the elderly,characterized by memory decline and cognitive impairment.It is now clear that microglia may play a key role in AD.Abnormal aggregation and accumulation of Aβin the brain will promote the polarization of microglia to M1 type,release a large number of pro-inflammatory cytokines and toxic nerve mediators,and induce neuroinflammation.Such substances will be accelerating the accumulation of Aβthrough the negative feedback pathway.As a result,a vicious circle between Aβ and neuroinflammation is formed,leading to neuronal apoptosis and disorder of the brain environment.Studies have shown that over-generated reactive oxygen species(ROS)are important signaling molecules that promote the interaction between Aβ and neuroinflammation.Therefore,by reducing the level of ROS in the brain,while promoting the normalization of microglia function or the depolymerization of Aβ fibril,it is considered to be an effective strategy to break the circulation between Aβ and neuroinflammation.Based on the characteristics of the pathogenesis of AD,we have designed two nanosystems for breaking the circulation between Aβ and neuroinflammation,respectively,for the early and middle-late AD treatments.This thesis consists of three chapters:Chapter 1: The global impact of AD,including prevalence,incidence,cost and trend analysis is summarized.The related pathogenic hypothesis of AD has been summarized.Some drugs and methods for the treatment of AD have been introduced.The basic structure and function of the blood-brain barrier are introduced.The application of nanosystems in anti-AD is summarized.Chapter 2: In view of the fact that there is not much Aβ deposition in the early stage of AD and the function of microglia is not severely damaged,a selenium-polydopamine system(Se@PDA@Bor)with imitate natural antioxidant enzyme activity is designed and synthesized.Studies have shown that Se@PDA@Bor can effectively scavenge many types of ROS and reactive nitrogen species,showing a broad-spectrum antioxidant activity,and protect nerve cells from oxidative damage induced by different stimuli.Se@PDA@Bor can also modulate the polarization state of microglia,showing a outstandting anti-inflammatory effect.More importantly,Se@PDA@Bor can successfully cross the BBB to the brain.First,by alleviating oxidative stress and neuroinflammation in the brain,it promote the function of microglia normalization,and then phagocytosis deposition of Aβ,and finally improve the memory deficit and behavioral executive dysfunction in AD mice.Chapter 3: A polydopamine-ruthenium nanosystem(PDA@Ru)with good photothermal conversion performance was designed and synthesized for the characteristics of high Aβ deposition and severely impaired microglia function in the middle and late stages of AD.PDA@Ru generates local heat under NIR radiation to depolymerize mature Aβ fibrils without damaging surrounding tissues.Moreover,PDA@Ru can reduce Aβ fibrils mediated neurotoxicity by as ROS scavenger.Studies have shown that PDA@Ru+NIR reduces the burden on microglia and relieves neuroinflammation by first thermally degrading Aβ deposited in the brain.Finally broke the vicious circle between Aβ and neuroinflammation.This study provides new insights into the treatment of neurodegenerative diseases caused by protein misfolding.