^(18)F-FDG与^(18)F-DPA-714 Micro PET/CT显像评价生酮饮食治疗阿尔茨海默病小鼠大脑代谢及神经炎症

Evaluation of Brain Metabolism and Neuroinflammation in Mice with Alzheimer's Disease Treated by Ketogenic Diet by^(18)F-FDG and^(18)F-DPA-714 Micro PET/CT

目的探讨生酮饮食(KD)能否通过调节阿尔茨海默病模型小鼠大脑代谢及神经炎症促进认知。材料与方法将20只APP/PS1雄性小鼠随机分为KD组(APP/PS1+KD)与普通饮食组(APP/PS1),每组10只;同时以10只野生型C57BL/6雄性小鼠作为对照组。使用生酮饲料喂养APP/PS1+KD组,普通饲料喂养APP/PS1组和对照组,共4个月。连续喂养4周、4个月后,记录小鼠的血酮,并使用Morris水迷宫评估小鼠认知,再行^(18)F-FDG和^(18)F-DPA-714 micro PET/CT分别评估KD对阿尔茨海默病小鼠各脑区葡萄糖代谢及神经炎症的影响;完成PET/CT显像后取脑组织,选择海马CA1区制成石蜡切片进行免疫荧光检测胶质纤维酸性蛋白、离子化钙结合适配分子表达情况。结果4个月时,与对照组相比,APP/PS1组第3~4天逃避潜伏期显著延长(P<0.01、P<0.05)。与对照组相比,APP/PS1组在纹状体、海马、背侧丘脑、中央灰质、上丘、嗅球、中脑等脑区对^(18)F-FDG的标准化摄取值比值显著下降(P<0.05或P<0.01);与APP/PS1组相比,APP/PS1+KD组海马、背侧丘脑对^(18)F-FDG的标准化摄取值比值显著升高(P<0.01)。与对照组相比,APP/PS1组纹状体、海马、下丘脑等脑区对^(18)F-DPA-714的标准化摄取值比值显著上升(P<0.05或P<0.001);与APP/PS1组相比,APP/PS1+KD组降低了海马区相对^(18)F-DPA-714摄取(P<0.01)。与对照组、APP/PS1+KD组相比,APP/PS1组小鼠脑(海马)胶质纤维酸性蛋白、离子化钙结合适配分子表达显著升高(P均<0.01)。结论KD可通过提高APP/PS1小鼠大脑代谢并抑制神经炎症,促进其认知行为学改善。

Purpose To investigate whether ketogenic diet(KD)can promote cognition by regulating brain metabolism and neuroinflammation in Alzheimer′s disease model mice.Materials and Methods Twenty male APP/PS1 mice were randomly assigned to either a KD group(APP/PS1+KD)or a regular diet group(APP/PS1),with 10 mice in each group.Additionally,10 wild-type C57BL/6 male mice served as the control group.The APP/PS1+KD group was fed with a ketogenic feed,the APP/PS1 group received a regular diet,and the control group was maintained on standard chow for a duration of 4 months.Blood ketone levels of mice were monitored after 4 weeks and 4 months of continuous feeding.Cognitive function was assessed via the morris water maze.^(18)F-FDG and^(18)F-DPA-714 micro PET/CT were performed to evaluate the effects of KD on glucose metabolism and neuroinflammation across various brain regions in the Alzheimer's disease mice.Following PET/CT imaging,brain tissue samples were collected,and the hippocampal CA1 region was selected for paraffin sectioning to detect the expression of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 through immunofluorescence analysis.Results In the Morris water maze in the fourth month,compared with the control group,the APP/PS1 group had a significantly longer escape latency on days 3-4(P<0.05 or P<0.01).Compared with the control group,the APP/PS1 group showed a significant decrease in relative^(18)F-FDG uptake in brain regions such as the striatum,hippocampus,dorsal thalamus,central gray matter,superior colliculus,olfactory bulb,and midbrain(P<0.01,P<0.05).Compared with the APP/PS1 group,the APP/PS1+KD group showed a significant increase in relative^(18)F-FDG uptake in the hippocampus and dorsal thalamus(P<0.01).Compared with the control group,the APP/PS1 group showed a significant increase in relative uptake of^(18)F-DPA-714 in brain regions such as the striatum,hippocampus and hypothalamus(P<0.05 or P<0.001).Compared with the APP/PS1 group,the APP/PS1+KD group decreased the relative uptake of^(18)F-DPA-714 in the hippocampus(P<0.01).Compared with the control group and APP/PS1+KD group,the fluorescence intensity of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 protein in the brain(hippocampus)of APP/PS1 group mice was significantly increased(both P<0.01).Conclusion KD has the potential to ameliorate cognitive and behavioral deficits in APP/PS1 mice by enhancing brain metabolism and attenuating neuroinflammation.