Investigate The Mechanism Of Kidney Nourishing And Removing Phlegm Method On Prevention And Treatment Of AD Based On VSP10p Family Proteins Affecting The APP Hydrolysis Pathway

Objective:Alzheimer’s Disease(AD),also known as senile dementia,is a kind of degenerative disease of central nervous system mainly manifested as memory loss,insomnia,cognitive impairment,and changes in personality and behavior.With the increase of the aging of the population,the current 10 million AD patients in China takes about a quarter of the world’s population who are suffering from AD.It is of great significance to explore effective approaches of prevention and treatment of AD.My advisor,Professor Wang Ping and his research team hypothesized based on over-20-year studies that "AD is essentially due to Kidney deficiency and the phlegm turbid is the secondary pathogensis",which leads to the corresponding therapy for AD: tonifying the Kidney and replenishing vital essence to reinvigorate the brain,and,restoring vitality of the brain with removing phlegm from obstruction.Our previous studies have confirmed that the mechanism of the prevention and treatment ofAD by tonifying Kidney and removing phlegm may be related to the intervention of PI3K/Akt pathway and ubiquitin-proteasome pathway.This study was designed to further exploring the possible mechanism of the prevention and treatment of AD targeting VPS10p-Aβ pathway by tonifying Kidney and removing phlegm.Methods:1.Theoretical basis for the study: Through systematic summarization of the understanding of ancient doctors on AD recorded in ancient literatures,we explored the theoretical basis of the prevention and treatment of AD by tonifying Kidney and removing phlegm.2.Experimental study: We investigated the ability of learning and memory,pathomorphological changes of APP/PS1 double transgenic AD mice under the treatment of tonifying Kidney and removing phlegm,as well as its regulation on VPS10 p family such as SorLA and SorCS-1 proteins,of which the outcome may further enrich the mechanism of this therapy on AD prevention and treatment.Results:1.The APP/PS1 double transgenic mice treated with kidney-tonifying and phlegm removing therapy behaved significantly better learning and memory ability than the model ones.2.The treated APP/PS1 double transgenic mice demonstrated reduction in hippocampus neuron apoptosis and nerve fiber entanglement,together with significant decrease in hippocamal intercelluar Aβ1-42 protein deposition.3.Peripheral blood Aβ1-42 protein content(by ELISA)was lowered statistically in APP/PS1 double transgenic mice that received the therapy.4.Western blot showed that hippocamal SorLA,SorCS-1 proteins were detected increased and APP and Aβ1-42 proteins reduced in treated mice than that in control group.5.Hippocamal SorLA gene detected by Real Time q PCR was significantly upregulated in treated mice.Conclusions:1.The understanding of AD in ancient China was mainly focused on symptom descriptions and pathogenetic discussions other than reaching a consensus on the naming of the disease.The essential etiology of AD lies in that it is manifested in the brain but rooted in kidney dorminated five Zang organs deficiency.The phlegm turbid accelerates the AD progression.Tonifying Kidney and removing phlegm is proved effective in preventing and treating AD.2.The therapy of tonifying Kidney and removing phlegm improves the learning and memory ability of APP/PS1 double transgenic mice.3.Tonifying Kidney and removing phlegm upregulates SorLA gene and increases the SorLA and SorCS-1 protein expression in APP/PS1 double transgenic mice,while reducing the expression of the peripheral blood and hippocamal Aβ1-42 protein and hippocamal APP protein expression.4.Regulation on VPS10 p family protein(SorLA and SorCS-1)for blocking APP being hydrolyzed to Aβ may be one of the mechanisms of kidney tonifying and phlegm removing in treating and preventing AD effectively.