VEGF Alleviates Mitochondrial Dysfunction And Suppression Of Mitochondrial Biogenesis In Models Of Alzheimer’s Disease

BackgroundAlzheimer’s diease(AD)is a neurodegenerative disease and the most common type of dementia today.Although the etiology and pathogenesis of AD is not completely clear,mitochondrial damage is an important pathological process of AD.It is found in the brain of AD patients that various factors such as amyloid deposition cause mitochondrial dysfunction in neurons,such as insufficient energy supply,increased peroxide,mitochondrial transport disorders,impaired mitochondrial biogenesis and mitochondrial dynamics.Neuronal damage leads to decreased cognitive function,and improving mitochondria is one of the keys to treating AD clinical symptoms.Vascular endothelial growth factor(VEGF)is an important factor that promotes angiogenesis.In addition to high expression in tumor diseases,VEGF has been found to have a protective effect on the nervous system.VEGF can not only improve the nervous system by improving cerebral ischemia,but also directly produce neurotrophic,neuroprotective,anti-apoptotic,and stimulate neurogenesis effects on neurons and glial cells.The effect of VEGF on mitochondrial structure and function in AD is unclearObjectiveIn this study,we explored the effects of VEGF on mouse cognition and cell viability in AD models,and studied the effects of VEGF on mitochondrial structure and function,mitochondrial biogenesis,autophagy,and mitophagy in AD.Methods1.A total of 24 APP/PS1 mice with 4 months of age were used as AD model mice and randomly divided into empty vector(VEH)group and 12 VEGF groupswith 12 mice in each group.Over-expressed VEGF or an empty vector of adeno-associated virus was injected into the hippocampus of mice by a microinjector2.Moiss water maze was used to detect the cognitive function of mice,thioflavin S staining was used to detect the amount of senile plaques deposited in the brain,and the content of soluble Aβ1-40 andAβ1-42was measured by enzyme-linked immunosorbent assay(ELSIA)3.SH-SY5Y cells were divided into control,AD group constructed with exogenous AP25-35,and Aβ+VEGF group which given exogenous VEGF165 on the basis of AD group.In three groups of cells,CCK-8 was used to detect the effects of VEGF on Aβ cytotoxicity.Fluorescence detection of ROS levels in response to VEGF improved Aβ caused changes in cell oxidation,proving that VEGF in AD can protect cells.4.The changes of mitochondrial structure in hippocampus and cells were observed by electron microscope,the copy number of mitochondrial DNA(mtDNA)in cells was detected by PCR,mitochondrial membrane potential also was detected,and mass of mitochondria were detected by immunofluorescence.The mitochondrial protective effect of VEGF in AD was verified from four aspects:mitochondrial structure,gene expression,mitochondrial membrane potential level and quantity5.Western bolt experiments were used to detect the most critical protein expressions of mitochondrial biogenesis and autophagy and mitochondrial autophagy.The effect of VEGF on mitochondrial biosynthesis,autophagy,and mitochondrial autophagy was demonstrated.Results1.Overexpression of VEGF in the hippocampus of mice.2.VEGF improves cognitive impairment and reduces Aβ in APP/PS1 mice.3.VEGF165 alleviates Aβ25-35 induced cytotoxicity and reduces ROS levels.4.VEGF reduces the proportion of damaged mitochondria in AD,increases gene expression,improves mitochondrial membrane potential drop,and increases total mitochondria.5.VEGF relieves mitochondrial biogenesis suppression induced by Aβin AD models,but no significant effects on levels of autophagy and mitophagy.ConclusionVEGF improves cognitive function,relieves many aspects of mitochondrial damage in AD,and stimulates mitochondrial biogenesis to improve mitochondrial damage in AD.