淀粉样前体蛋白胞内结构域对阿尔茨海默病模型小鼠神经发生和学习记忆的影响

Effects of Amyloid Precursor Protein Intracellular Domain on Neurogenesis,Learning and Memory in Alzheimer’s Disease Model Mice

【目的】探讨淀粉样前体蛋白胞内结构域(AICD)对阿尔茨海默病(AD)模型动物神经发生、学习记忆的影响。【方法】本研究使用免疫荧光染色检测AICD转基因小鼠来源的体外培养的神经前体细胞(NPCs)、胚胎大脑皮质、成年海马齿状回(DG)中增殖和分化的细胞数目;水迷宫实验检测老年AICD转基因小鼠对学习记忆能力影响;生物信息学预测和分析潜在的分子机制。【结果】免疫荧光染色结果显示AICD转基因模型体外NPCs、胚胎皮质、海马DG区域的神经干细胞和神经元数量减少(P<0.05),即AICD抑制不同时期AD模型小鼠的神经发生。水迷宫结果显示AICD增加AD模型小鼠逃逸潜伏期,减少其跨越平台次数,并减少DG区域神经元数目(P<0.05)。生物信息学结果显示,AICD参与调节AD发病进程中神经发生和学习记忆的靶点有1723个,关键靶点有TP53、CTNNB1、Akt1、EGFR、SRC、EP300、HDAC1、STAT3、HSP90AA1和MAPK1;另外,KEGG通路注释分析发现PI3KAkt、HIF-1等信号通路在AICD调节神经发生和学习记忆起关键作用。【结论】表明AICD可以抑制AD模型小鼠海马神经发生进而损害学习记忆能力,这可能与PI3K-Akt和HIF-1等信号通路有关。本研究为进一步理解AICD在AD发病进程中作用提供实验依据。

【Objective】To investigate the effects of amyloid precursor protein intracellular domain(AICD)on neurogenesis,learning and memory in Alzheimer’s disease(AD)model mice.【Methods】Immunofluorescence staining was used to detect the proliferation and differentiation of neural progenitor cells(NPCs)cultured in vitro,numbers of neural stem cells and neurons in embryonic cerebral cortex and adult hippocampal dentate gyrus(DG)derived from AICD transgenic mice.The morris water maze was applied to evaluate learning and memory ability of old AICD transgenic mice,and bioinformatics to predict and analyze the underlying molecular mechanisms.【Results】Immunofluorescence staining showed that NPCs,numbers of neural stem cells and neurons in embryonic cerebral cortex and hippocampal DG region were decreased(P<0.05),indicating that AICD inhibited neurogenesis in AD model mice at different periods.Morris water maze revealed that AICD increased escape latency of AD model mice,reduced numbers of platform crossing and neuron numbers in DG region(P<0.05).Bioinformatics results found 1723 targets of AICD involved in the regulation of neurogenesis,learning and memory in the pathogenesis of AD,in which the key targets were TP 53,CTNNB 1,Akt 1,EGFR,SRC,EP 300,HDAC 1,STAT 3,HSP 90 AA 1 and MAPK 1.KEGG pathway annotation analysis showed that signaling pathways like PI 3 K-Akt and HIF-1 play a crucial role in the regulation of neurogenesis,learning and memory by AICD.【Conclusions】AICD could inhibit hippocampal neurogenesis in AD model mice,thus impair their learning and memory ability,which may be related to PI 3 K-Akt and HIF-1 signaling pathways.This study provides an experimental basis for further understanding the role of AICD in the pathogenesis of AD.