Autophagy Dysfunction Is Involved In Surgery:Induced Behavioral Deficits In Aged C57BL/6J Mice

Objective: Postoperative cognitive dysfunction(POCD)is a central nervous system complication following major surgery,which is manifested as postoperative disturbance of cognition,orientation,thinking,memory and sleep.Factors closely related to POCD include preoperative age,physical condition,alcohol abuse,etc.Perioperative factors such as operation time,anesthesia,intraoperative hypotension and electrolyte disturbance;Postoperative infection,pain relief pump and other factors.The pathological processes involved in POCD,such as neuroinflammation,mitochondrial dysfunction,oxidative stress,blood-brain barrier injury,and neurotrophic support disorders,have been extensively studied.Among these mechanisms,neuroinflammation is the most studied.Animal experiments with a large number of trauma models have demonstrated the activation of central microglia cells,accompanied by the release of a large number of inflammatory mediators,resulting in the decline of learning and memory ability in rodents after surgery.The only known risk factor for POCD is advanced age,or senescence,when the body is associated with loss of protein homeostasis,altered nutrient sensing,damage to organelles and mitochondria,cellular senescence,stem cell failure,and other dysfunction.Many of these changes may be due at least in part to the deterioration of basal autophagy during cellular stress and/or to impaired induction of proper autophagy flux.The recent decade’s exploration of autophagy’s networks and connections between metabolism,quality control,inflammation,and immune processes has demonstrated that autophagy is key to many human diseases,including neurodegeneration,obesity and diabetes,chronic inflammation,cancer,infection,and aged.Autophagy dysfunction and inflammation have been associated with the pathogenesis of a range of neurodegenerative diseases.Autophagy has anti-inflammatory effects and inhibits proinflammatory processes by regulating innate immune signaling pathways and inflammasome activity.POCD has a similar molecular mechanism to neurodegenerative alzheimer’s disease(AD).We speculate that in the pathological process of multiple POCD in aged patients,the abnormal autophagy function(such as the abnormal autophagy-associated protein)causes the abnormal increase of inflammatory factors in the central nervous system,which must play an important role.Although most studies evaluating the role of autophagy in neurodegeneration and senescence have focused on neurons,recent studies have shown that autophagy may also modlify the release of soluble inflammatory mediators and engulf CNS specific debris.Recent studies have shown that autophagy controls the inflammatory response of peripheral and central innate immune macrophages.A large number of studies have confirmed the role of microglia in POCD,so autophagy may play an important role in the development of POCD directly and/or indirectly.m TOR is a key target for autophagy control,located downstream of phosphatidylinositol 3 kinase(PI3K)and kinase AKT(AKT).This pathway is activated by receptors for neurotrophic factors and growth factors to promote cell growth,differentiation and survival,while downregulating autophagy signaling.Therefore,the activation of the PI3K/AKT/m TOR pathway can in principle promote survival,neuronal protection and mTOR activation,and inhibit autophagy.This study proposed the surgical trauma associated with age trauma caused by the cognitive dysfunction and potential role between autophagy function: is the degeneration of the nervous system,on the basis of the surgical trauma further aggravate the aged mice learning memory ability,the process,with the central nervous system reduced autophagy related proteins,inflammatory cytokines increase,giving autophagy enhancer,reversal of aged mice behavior caused by abnormal operation;The inhibition of PI3K/AKT/mTOR pathway to enhance autophagy level can also improve the decline of learning and memory ability caused by surgical trauma in mice.Methods: Part I: the role of autophagy in impaired learning and memory in aged mice caused by surgical trauma.Adult and aged C57BL/6J mice underwent partial hepatectomy or intraperitoneal injection of rapamycin 6 weeks prior to partial hepatectomy.On the 3rd,7th and 14 th day after the operation,mice were conducted in the open field experiment and Morris water maze exploration experiment.The expression of autophagy related factors atg5,p-tau /Tau and synaptopsin protein related to cognitive function in the hippocampus was detected.mRNA expression levels of related pro-inflammatory factor IL-1β,autophagy related factors atg13 were determined by PCR.Part Ⅱ: the role of PI3K/AKT/mTOR signaling pathway in regulating autophagy on postoperative cognitive dysfunction in aged mice Adult and aged C57BL/6J mice underwent partial hepatectomy or lateral ventricular injection of LY294002 after partial hepatectomy.Open field experiment and Morris water maze exploration experiment were conducted on the 7th day after surgery.The expression levels of Atg5,mTOR(Ser2448),Mtor,Synaptophysin,P70S6K(Thr389),P70S6 K,Tau(Ser396)and Tau in the hippocampus were detected,and the mRNA levels of Atg5 and Synaptophysin were determined by PCR.Results: Part I: the role of autophagy in impaired learning and memory in aged mice caused by surgical trauma Age aggravated the impairment of learning and memory induced by the operation on the 3rd,7th and 14 th day after the operation,as well as the decrease of autophagy-related factors atg5,synaptopsin protein,and the increase of p-tau /Tau protein.mRNA expression levels of atg13 and inflammatory cytokine IL-1β were increased.Intraperitoneal injection of rapamycin can promote autophagy,which is manifested by the increase of autophag-related factors atg5,atg13 and the decrease of IL-1β,p-tau /Tau,the increase of synaptopsin protein and the improvement of behavioral performance.Part Ⅱ: the role of PI3K/AKT/mTOR signaling pathway in regulating autophagy on postoperative learning and memory impairment in aged mice After the operation trauma,the age aggravated the learning and memory loss and decreased the autophagy level.PI3K/AKT/mTOR pathway was activated,and p-mTOR /mTOR were elevated.Its downstream p-p70s6 k /P70S6 K level is also correspondingly increased,autophagy related protein Atg5 is decreased,the protein p-tau /Tau that affects cognitive function is increased,and the level of synaptopsin protein is decreased.Injection of PI3 K inhibitor LY294002 into the lateral ventricle can reduce the activation of PI3K/AKT/mTOR pathway,reduce the level of p-mtor /m TOR,p-p70s6 k /P70S6 K,promote autophagy,increase the level of Atg5 and synaptopsin protein in the brain,reduce p-tau /Tau,and improve behavioral performance.Conclusion: 1.Surgical trauma resulted in decreased autophagy and impaired cognitive function,which were particularly significant in elderly mice.The decrease of autophagy promotes the increase of inflammatory factors and the phosphorylation of tau protein in the central nervous system,reduces the expression of synaptic protein,and aggravates the cognitive damage caused by surgical trauma in aged mice.Rapamycin improved the cognitive impairment caused by surgical trauma in elderly mice by promoting autophagy expression,reducing the phosphorylation of inflammatory factors and tau protein,and enhancing the synaptic protein.2.The PI3K/AKT/mTOR pathway is involved in the cognitive impairment caused by surgical trauma in aged mice by regulating autophagy.Inhibition of PI3K/AKT/mTOR pathway activation enhances autophagy level,reduces tau protein phosphorylation,and promotes synaptic protein expression to improve cognitive decline after surgical trauma.