Mechanism Of Estrogen Deficiency On Glucose Metabolism And Learning And Memory In Brain Of APP/PS1 Double Transgenic Mice

Objective: To study the metabolism of glucose in the brain of APP/PS1 double transgenic mice and the changes related to learning and memory in different time periods of estrogen deficiency and clarify its possible molecular mechanisms.Methods: Three-month-old female APP/PS1 double transgenic mice and the same month old WT mice underwent bilateral ovariectomy(AD-OVX),sham-operated AD mice(AD-Sham),wild-type mice(WT-Sham)and(WT-OVX)were used as controls.1 week after surgery(simulating early menopause),1 month and 3 months(simulating middle and late menopause respectively).The uterus weighing reflected estrogen levels;Morris water maze was used to detect the effects of OVX on spatial learning and memory in mice;Immunohistochemical staining was used to detect senile plaques and neurons in the brain;Transmission electron microscopy(TEM)was used to detect the ultrastructural changes of synapses and mitochondria in hippocampus of mice;Golgi-cox stain wasused to detect changes of dendritic spines in hippocampus of mice;2-fluoro-2-deoxy-D-glucose-positron emission tomography(FDG-PET)was used to detect the metabolism of glucose in the brain of mice;Western blot was used to detect the aromatase and glucose transporters(GLUT-1,GLUT-3),synapse-associated proteins of GAP43 and PSD95),mt-PDE1-?protein,and energy metabolism pathway-related signaling molecules(mt-ER?,IGF-1,IGF-1R,p-GSK-3?(ser9),GSK-3?)expressions.Results: 1week after OVX,the uterus weight of the AD-OVX group began to decrease,but it was not statistically significant;the aromatase in the brain of the mouse showed an increase trend in reactivity;1 month and3 months after OVX,in AD mice and WT mice,the uterus of the OVX group was atrophied and the weight was significantly reduced;the expression of aromatase showed a downward trend;Immunohistochemical showed that within 1 week and 1 month after OVX,the mice in each group had no obvious senile plaques;3 months after OVX,a large number of senile plaque deposits in the brain of AD-OVX mice,as well as in the brain of AD menopausal women.The expression of MAP2 and NeuN proteins were observed,1 week after OVX,the expression of NeuN protein in the brain of AD-OVX group was increased compared with AD-Sham group;however the expression of NeuN was significantly decreased in 1 month and 3 months after OVX,the trend of WT mice in the surgical group was consistent with that of AD mice;Morris water maze showed that in theAPP/PS1 double transgenic AD mice,1 week after OVX,there was no significant difference in the escape latency,escape length and passing times between AD-OVX group and AD-Sham group;At this time,synapses and the number of presynaptic membrane vesicles,the number of dendrites and dendritic spines in hippocampus were also no significant difference;The length of synaptic activity in hippocampus and the expression of synaptic-associated proteins(GAP43,PSD95)were increased in reactivity;1 month and 3 months after OVX,the time and escape length in the AD-OVX group were significantly prolonged,and passing times were also reduced;the number of synapses,presynaptic membrane vesicles,the length of the synaptic active region,the expression of synaptic-associated proteins(GAP43,PSD95)and the number of dendrites and dendritic spines in the hippocampus associated with learning and memory,were decreased significantly.FDG/PET showed that compared with WT mice,glucose uptake was significantly reduced in AD mice cerebral.One week after OVX,the brain glucose uptake in the AD-OVX group was increased compared with the AD-Sham group,at this time,the glucose transporters(GLUT-1,GLUT-3)were an increased trend;1 month and 3 months after OVX,the glucose uptake in the brain of the AD-OVX group was reduced,and the expression of glucose transporters(GLUT-1,GLUT-3)were also significantly decreased;Transmission electron microscopy and Western blot separately showed that there was no significant change in themitochondrial structure in the hippocampus between the AD-OVX group and AD-Sham group;The expression of mt-PDE1-?,mt-ER?,IGF-1,IGF-1R,and p-GSK-3?(ser9)in the brain were an increased trend;1month and 3 months after OVX,mitochondria of AD-OVX group showed mild and severe edema,mt-PDE1-?,IGF-1,IGF-1R,p-GSK-3?(ser9)proteins expression showed a significant decrease trend;interestingly,in the 3 months after OVX,the expression of mt-ER? protein in the brain of AD-OVX group was up-regulated.Conclusion: Bilateral oophorectomy(OVX)can simulate the menopausal state very well.Early estrogen deficiency has a trend of stress response in brains of AD mice in a compensatory manner,but with the prolongation of estrogen deficiency,the glucose metabolism,function and structural of learning and memory in AD mice are damaged,further aggravating the pathological features of AD.This effect may be related to the aberrantly expressed mt-ER? mediated energy metabolism IGF-1/IGF-1R/GSK-3? signaling pathway.