Experimental Therapeutic Study Of Alzheimer's Disease Model Mice

Alzheimer's disease(AD)is a neurodegenerative disease characterized by gradual declines in social,cognitive,and emotional functions,leading to a loss of expected social behavior.Additionally,social isolation(SI)has been shown to have adverse effects on individual development,growth,as well as health and aging.However,the interactions between SI and AD still remain unknown.Previous experiments have shown that SI causes an early onset of AD-like phenotypes in young APP/PS1 mice.In this study,we demonstrate that 3 month isolation housing further promoted cognitive deterioration in 20-month old APP/PS1 mice.Isolated aged AD mice developed increased brain A? accumulation in the hippocampus,associated with increased ?-secretase and decreased neprilysin expression,compared with group-housed controls.Furthermore,exacerbated hippocampal atrophy,synapse and myelin associated protein loss,and glial neuroinflammatory reactions were observed in the hippocampus of isolated aged APP/PS1 mice.The present study suggests that even during the late stage of AD,isolation housing exacerbates AD pathophysiology,and thus group and social life is necessary for delaying or counteracting the AD process.Alzheimer's disease(AD)is a degenerative disease in the elderly,whose pathological features are characterized by extensive loss of neurons in the brain,and clinical features are characterized by progressive cognitive decline accompanied with abnormal psychological and behavior disorders.The etiology and pathogenesis of AD is still undefined,and there is no effective strategy to treat the disease.However,it is known that the age is the biggest risk factor for AD.APP/PS1 transgenic mice can simulate the pathological changes and behavior features of familial AD,thus extensively used in the AD research.However,most of previous studies are limited to use adult APP/PS1 mice,and the systematic analysis of AD-like phenotype in the aged stages is still lack.Exploring this issue not only helps to fully evaluate the extent of this model mimicking AD pathology,but also to further understand the late-stage progress of AD.Therefore,the purpose of the study is to systematically analyze the AD pathophysiological changes of 24-month old APP/PS1 mice.Behavioral results showed that APP/PS1 mice had mild decline in short-term working memory,less interest in searching for novel environment,mild anxiety,severe impairment in social interaction,and slight increase in motor activity,when compared to the wild type mice.The pathological and histological results showed that there was high accumulation of amyloid plaques in the dorsal hippocampus,with decreases in hippocampal volume and neuronal density,as well as levels of synaptophysin and brain derived neurotrophic factor in aged APP/PS1 mice.Astrocyte atrophy and microglia activation were also observed surrounding amyloid plaques.In addition,the expression of ?-,?-,?-secretase and neprilysin in the hippocampus had no difference between APP/PS1 mice and wild type mice,but,insulin degradation enzyme decreased significantly in APP/PS1 mice.These results suggested that APP/PS1 mice at the age of 24 months can be more fully simulated AD pathophysiology and abnormal behavior,including large ?-amyloid deposition in the hippocampus,hippocampal atrophy and massive neuronal loss,and emotional and behavioral abnormalities,compared to their at young and adult ages.Moreover,the reduced insulin degradation enzyme could contribute to further accumulation of amyloid plaques in the hippocampus of aged APP/PS1 mice.This finding would extend our knowledge of AD-like phenotype in APP/PS1 mice,and also have positive effects on AD pathogenesis and preclinical therapeutic research.