Study On The Abnormal Degradation Of Aβ By Lysosomes In The Pathogenesis Of Alzheimer’s Disease

Aims:Alzheimer’s disease（AD）has become one of the main causes of disability and inability to live independently in the elderly,which can cause serious harm and heavy burdens to families and society at large.The degradation obstacle of Aβcaused by the lysosomal function abnormality is playing a key role in the pathologic mechanism of AD.This study attempts to provide a new way of thinking to explore the pathogenesis of AD by researching the relationship between the abnormal changes in lysosomal acidic environment and the onset of AD through studying lysosomal dysfunction.Methods:HT22 cells and TgAPPsw Mouse’s microglia are studied through measuring intracellular V-ATPase changes,cytoplasm and lysosomes pH value changes.We analyzed these changes and identify the effects of these factors in cell viability and Aβ.The relationship between the acid environment change of lysosome and the incidence of AD was analyzed by the results of statistical experiments.Results:The decrease of cell viability can be induced by Aβ_25-355-35 while a significant increase of cell viability comes after adding proton pump inhibitors BafilomycinA1.The V-ATPase expression was increased after HT22 cells had been treated by 40μmol/L Aβ_25-35（P<0.05）.Moreover,in the cells treated by Aβ_25-35+BafA1,V-ATPase expression was increased more than only Aβ_25-35 treatment group.It was showed that the expression amount of V-ATPase is higher in APP mice microglia than in wild type mice microglia.The expression amount of V-ATPase was both increased in APP and WT mice microglia after activating microglia.In addition,the V-ATPase expression increase in APP mice was more obvious than that in WT mice.The acid environment of the lysosome is affected by the expression of V-ATPase.After the acid environment of lysosome has been changed,the scavenging ability of Aβwas weakened,which leads to the neurotoxicity of Aβin microglia cells.And the neurotoxicity of Aβcan decrease the autophagy of the lysosome and leads to death of nerve cells and bring the occurrence of cognitive dysfunction and AD.Conclusion:Aβis unable to be hydrolyzed and cleared efficiently by the changes of lysosomal acid environment.Autophagy can be induced by Aβin cells,and this autophagy is related to the concentration and actuation duration of Aβ.Moreover,the autophagy ability of cells is influenced by the expression of V-ATPase,and the decrease of autophagy leads to the abnormal aggregation of Aβin brain cells which may cause and promote the development of AD.