Age-related Changes In Alzheimer’s Disease-like Pathology In Male APP/PS1/Tau Triple Transgenic Mice

Objective: The typical pathological signs of Alzheimer’s disease are extracellular amyloid plaques deposition and intracellular neurofibrillary tangles,in addition to synaptic dystrophy,astrocyte proliferation,microglia activation and mature neuron markers Changes in things.Its main clinical manifestations are memory,language,visual space and executive dysfunction.The current treatment for AD is palliative and treats the symptoms but not the root cause.Among them,immunotherapy has become the most promising method.However,although some monoclonal antibodies have been proven to be effective,serious shortcomings such as vasogenic edema and microbleeds occurred during clinical trials.Therefore,their development was suspended.The frequent failures of preclinical research into clinical trials indicate the key role of animal models in drug development.Nowadays,more and more types of transgenic mouse models are contributing to AD research.Among them,APP/PS1/Tau triple transgenic mice is one of the most commonly used AD transgenic models.APP/PS1/Tau triple transgenic mice simultaneously express three rare family mutant genes: human PS1M146 V,human APPswe and human Tau P301 L,It has important reference value in evaluating the pathology of co-evolved amyloid and Tau.This experiment mainly explores the AD-related pathomorphological changes in the brain tissue of male APP/PS1/Tau transgenic mice aged 2-15 months to provide important information for future experiments on drugs,mechanism,behavior,gender,etc.by using this mouse model.Methods: Male 3x Tg-AD mice were randomly divided into 7 groups according to the age of 2,4,6,8,10,12,and 15 months,with 3 mice in each group as the experimental group;age-matched male C5B7L/6J mice Randomly divided into 7 groups according to the age of 2,4,6,8,10,12,and 15 months,with 3 mice in each group as a control group.The immunohistochemical method was used to detect the age-related changes of pathology closely related to AD in the hippocampus CA1 area and sensory cortex of various mouse brain tissues,including: Aβ,phosphorylated Tau,transgenic products of human Tau P301 L mutants,and astrogel Plasma cells,neuronal markers,motor proteins.Results: Compared with WT mice,The immunostaining intensity of 3x Tg-AD mouse Aβcells(6E10),Tau(HT7),p-Tau(AT8,Ser202/Thr205),astrocytes(GFAP),dynamin-1(Dynamin-1)was significantly enhanced,P < 0.0001,and the neuronal nucleus(NEUN)immunostaining intensity was significantly weakened,P < 0.0001.There was no obvious senile plaque deposition in the hippocampal CA1 area and sensory cortex of male 3x TgAD mice aged 2-15 months.The staining degree of Aβ cells(6E10)in hippocampus CA1 area gradually increased since 8 months of age,and the degree of staining in sensory cortex remained unchanged,P < 0.05;The staining degree of Tau(HT7)in the CA1 area of the hippocampus has weak staining at 2 to 6 months of age,and the staining degree remained stable from 6 months to 15 months old,the degree of staining in the cortex area increased from 2 to 4 months old,and the staining degree remained stable from 4 to 15 months old,P < 0.05;CA1 area p-Tau(AT8,Ser202/Thr205)The degree of phosphorylation began to increase at 6 months old,and the degree of phosphorylation in the sensory cortex increased at 12 months old,P < 0.05;the astrocytes(GFAP)in the CA1 area and the sensory cortex area gradually increased their reactivity at the age of 2 months to 15 months;The number of mature neuron markers(NEUN)in CA1 area gradually decreased from 2 months to 6months,and was stable from 6 months to 15 months.The number of NEUN in CA3 area gradually decreased from 2 months to 15 months,P < 0.05;The staining degree of Dynamin-1 in CA1 area and sensory cortex gradually increased from 2 to 10 months,and the staining degree was basically stable from 10 to 15 months,P < 0.05.Conclusions: At the age of 2 months,the CA1 area and sensory cortex of 3x Tg-AD mice had emerged major pathological changes related to AD.The pathological changes of Aβand Tau protein were earlier than other pathological changes,but there were no senile plaques at the age of 2-15 months.Except for astrocytes,the rest of the pathological changes change mainly at 6,8,and 10 months of age.The pathological changes of astrocytes continue to progress from the age of 2 months.The time of pathological changes of Aβ and Tau are earlier in the CA1 area than in the sensory cortex.The time of pathological change astrocyte and synapse loss is the same in the CA1 and sensory cortex area,and the time of pathological change neuron loss is the same in the CA1 area and CA3 area.However,the intensity of pathological changes in the sensory cortex is weaker than that in the CA1 area.