Effects And Mechanism Of Proline Hydroxylase Inhibitor FG-4592 On Symptom Improvement And Disease-modifying For Alzheimer's Disease Model

Alzheimer's disease(AD)is the most common neurodegenerative disease in elderly patients.Up to date,acetylcholinesterase inhibitors and N-methyl-D-aspartic acid(NMDA)inhibitors are the most common used drugs for AD.Although these drugs can effectively ameliorate the symptoms of AD,pathological process of AD cannot be reversed.EPO and its derivatives received much attention in neural degenerative diseases owning to the disease-modifying function.The proline hydroxylase(PHD)inhibitor,an important EPO derivative,can stabilize HIF to modulate the expression of EPO and regulate a series of pathological and physiological processes.It has been confirmed that treatment of PHD inhibitors can enhance cognitive ability in healthy mice.However,whether PHD inhibitors can ameliorate the symptoms and reverse pathological process of AD model mice is still unclearThe LC-MS/MS method was established to determine the concentration of FG-4592 in plasma and brain after intraperitoneal administration.In scopolamine-induced dementia mice model for AD,open field test,Morris water maze and passive avoidance test were performed to evaluate the cognitive function.RT-PCR,Western blot and ELISA were applied to investigate the effect of FG-4592 on the expression of HIF and EPO,cholinergic neuron,and neuroinflammation.In APP/PS1 double transgenic mice model for AD,Morris water maze was used to evaluate the memory and learning ability.AP deposition,the level of Tau protein hyperphosphorylation and APP processing were investigated by RT-PCR,immunological histological chemistry,and ELISAThe results showed that FG-4592 was well absorbed in mice plasma and could cross the blood brain barrier.It took about 20 minutes to achieve the peak concentration in brain after intraperitoneal administration.In scopolamine-induced dementia mice model for AD,FG-4592 could improve memory deficits,which were reversed by HIF inhibitor Acriflavine hydrochloride.After drug administration,the expression of EPO,HIF-la and HIF-2a increased.FG-4592 inhibited the AChE activity and increased the level of ChAT,VAChT,p-CREB and CREB protein.In addition,the expression of inflammatory factors TNF-a,IL-1? and IL-8 decreased These indicated the symptom improvement was related to stabilizing HIF,up-regulating EPO,enhancing the function of cholinergic neuron,and inhibiting neuroinflammation.In APP/PS1 double transgenic mice,the cognitive deficits were ameliorated by FG-4592.Furthermore,FG-4592 markedly increased the production of EPO.It reduced A? deposition through down-regulating APP expression while improving a-secratase activity.FG-4592 also decreased Tau protein hyperphosphorylation.These findings demonstrated that the symptom improvement was related to modifying the key characteristics of ADIn summary,FG-4592 can ameliorate cognitive deficits and modify the pathological process of AD.This study clarified the potential of PHD inhibitor for the prevention and treatment of AD as well as possible related regulatory mechanisms,and widened the application in neurodegenerative diseases.This research helps to better understand the pathophysiological process of AD,and provides innovative ideas together with experimental basis to find effective targets to treat AD.