PI3K/AKT信号通路在AD发病中的作用
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摘要
第一部分PI3K/AKT信号通路对Aβ诱导细胞凋亡影响
【背景】
β淀粉样蛋白(β-amyloid, Aβ)的过度产生和聚集是引起阿尔茨海默病(Alzheimer's disease, AD)的重要发病启动因素。AKT是调节神经元再生和维持神经元存活的重要分子之一,然而对于上调AKT是否能对抗Aβ诱导的神经元凋亡,至今仍未见报道。
【目的】
探讨上调PI3K/AKT通路对Aβ诱导细胞凋亡的保护作用和机制
【方法】
在转染AKT、非转染AKT及用或不用Wortmanin (AKT特异性抑制剂)的条件下,同时用20uM Aβ处理HEK293细胞。AnnexinV- PI双染和流式细胞仪检测HEK293细胞活性和细胞凋亡,RT-PCR检测AKTmRNA表达变化。免疫印迹法(western blot)检测HEK293细胞内凋亡相关蛋白caspase-3和bcl-2家族(包括Bcl-xL, Bcl-w, Bad, and Bax)和AKT、JNK、ERK的表达变化。
【结果】
Aβ(1-42)在不同的浓度(10 uM,20uM,50uM)作用24h后,AnnexinV-PI双染和流式结果显示Aβ(1-42)可以明显的增加HEK293细胞活性降低和细胞凋亡；瞬转高表达AKT可以有效的减少Aβ(1-42)引起的细胞毒性和促凋亡作用；AKT高表达能显著降低HEK293细胞中caspase-3表达量；高表达AKT的HEK293细胞中Bad和Bax表达量显著低于Aβ(1-42)处理组,而且AKT组Bcl-xL,Bcl-w表达量较Aβ(1-42)处理组显著增加；HEK293细胞高表达AKT后JNK活性明显增加；Wortmanine抑制AKT活性后,消除了高表达AKT对抗Ap诱导的HEK293细胞凋亡。
【结论】
高表达AKT可以有效的对抗AB诱导的细胞毒性,减少细胞凋亡,其机制是通过JNK激酶,促使抗凋亡蛋白Bcl-xL, Bcl-w表达减少和促凋亡Bad和Bax蛋白表达增加来实现的。
第二部分上调PI3K/AKT信号通路对Aβ诱导的tau磷酸化的影响
【背景】
神经原纤维缠结(neurofibrillary tangles, NFTs)是阿尔茨海默病(Alzheimer's disease, AD)的主要病理学特征,NFTs的主要成分是异常过度磷酸化的微管相关蛋白tau,尽管一些研究报道β-淀粉样蛋白(β-amyloid, Aβ)可以通过抑制PI3K/AKT通路激活糖原合成激酶-3(Glycogen synthase kinase 3. GSK3),增加tau磷酸化,但上调AKT表达是否可以保护Aβ诱导的tau磷酸化,仍未见报道。
【目的】
本实验通过在HEK293/tau细胞株中上调PI3K/AKT通路观察神经元中tau磷酸化相关位点的改变及探讨其机制。
【方法】
本实验在HEK293/tau细胞上稳转野生型AKT后,在培养液中加入Aβ1-4220 uM,免疫印迹法检测tau磷酸化位点S396, S214, S404的改变,p-GSK3β-Ser9, m-PP2A-Leu309, PTP1B,表达的变化。
【结果】
(1)在IIEK293/tau细胞中瞬时高表达AKT24小时后,用Aβ处理HEK293/tau细胞,结果显示AKT明显逆转了Aβ诱导的tau多个位点(S396、S214、S404、S198、199、202)磷酸化,总tau含量没有明显改变。(2)转染AKT+Aβ处理组p-GSK3β-Ser9的水平和m-PP2A-Leu309水平比单独Aβ处理组显著升高,而dm-PP2A-Leu309水平明显降低(3)PTPIB表达在AKT+Aβ处理组比单独Aβ处理组明显升高。
【结论】
过表达AKT可以明显的逆转Aβ诱导的tau蛋白磷酸化,其机制是通过PTP1B增加PP2A活性和降低GSK3β活性水平。
Background
Overproduction and accumulation ofβ-amyloid (AP) have been proposed to be an initiating factor of neuron loss in Alzheimer's disease (AD). AKT is a pivotal molecule in regulating neuronal survival; however, it is still not known whether upregulation of AKT can protect the cells from the Aβ-induced apoptosis.
Object
Study on the role of upregulation akt against the Aβ-induced apoptosis in the HEK293 cells.
Methods
We divided the cells into five groups.including control group, AP(1-42) group,vector group,AKTwt group,AKTwt+wortmanine group,and treated the HEK293 cells with 20uM AP(1-42) besides control group.By using AnnexinV- PI double-colouring and flow cytometry,cell viability and cell apoptosis was assayed,the AKTmRNA was detected by RT-PCR. Western blot investigates AKT,caspase-3 bad,bax, Bcl-xL, Bcl-w expression and JNK phosphorylation.
Results
In the present study that upregulation AKT could significantly attenuate the cell apoptosis induced by Aβ(1-42),we also find that the caspase-3,bad,bax expressed in the Aβgroup obviously higher than in the akt group through western blot,moreover the results show that the expression level of Bcl-xL, Bcl-w is significantly decreased in the Aβgroup. Upregulation AKT reduced JNK phosphorylation, and the wortmanine eliminated the effects of overexpressed akt.
Conclusion
these results moreoverly suggest that upregulation AKT attenuate Aβinduced apoptosis mainly through reduced JNK phosphorylation,which regulated the gene balance of acceleration and inhibition apoptosis. the signaling of PI3K/AKT could be a promising therapeutic strategy for arresting AP toxicity in AD patients
Background
Alzheimer's disease is a neurodegenerative disease characterized by the accumulation of beta amyloid into amyloid deposits and by the hyperphosphorylation of the protein tau,leading to neurofibrillary tangles. In addition to tau, abnormally hyperphosphorylated neurofilament is also the protein component of NFTs.β-amyloid peptide could increased the phosphorylation of tau by activating the Gsk-3β. it is still not known whether upregulation of AKT can attenuates the Aβ-induced tau hyperphosphorylation.
Object
Study the changes and mechanism of upregulation akt on the Aβinduced tau phosphorylation.
Methods
After transiently transfected AKTwt in the HEK293 cells, which treated with 20uM Aβ(1-42). Western blot detects the phosphorylation sites of S396, S214, S404, tau-1, tau-5 and pSer9-Gsk3βT-Gsk3β, mL309PP2A, dmLeu309PP2A, PTP1B.
Results
the results shows that:(1) S396,S214,S404 sites obviously decreased in the cells of upregulation AKT. (2) p-GSK3β-Ser9 increased, m-PP2A-Leu309 increased. (3) upregulation AKT increased PTP1B expression
Conclusion
These results indicated that upregulation AKT attenuates the Aβinduced tau phosphorylation.which mainly through increased the activity of PP2A through the signaling of PTP1B.
【背景】
β淀粉样蛋白(β-amyloid, Aβ)的过度产生和聚集是引起阿尔茨海默病(Alzheimer's disease, AD)的重要发病启动因素。AKT是调节神经元再生和维持神经元存活的重要分子之一,然而对于上调AKT是否能对抗Aβ诱导的神经元凋亡,至今仍未见报道。
【目的】
探讨上调PI3K/AKT通路对Aβ诱导细胞凋亡的保护作用和机制
【方法】
在转染AKT、非转染AKT及用或不用Wortmanin (AKT特异性抑制剂)的条件下,同时用20uM Aβ处理HEK293细胞。AnnexinV- PI双染和流式细胞仪检测HEK293细胞活性和细胞凋亡,RT-PCR检测AKTmRNA表达变化。免疫印迹法(western blot)检测HEK293细胞内凋亡相关蛋白caspase-3和bcl-2家族(包括Bcl-xL, Bcl-w, Bad, and Bax)和AKT、JNK、ERK的表达变化。
【结果】
Aβ(1-42)在不同的浓度(10 uM,20uM,50uM)作用24h后,AnnexinV-PI双染和流式结果显示Aβ(1-42)可以明显的增加HEK293细胞活性降低和细胞凋亡；瞬转高表达AKT可以有效的减少Aβ(1-42)引起的细胞毒性和促凋亡作用；AKT高表达能显著降低HEK293细胞中caspase-3表达量；高表达AKT的HEK293细胞中Bad和Bax表达量显著低于Aβ(1-42)处理组,而且AKT组Bcl-xL,Bcl-w表达量较Aβ(1-42)处理组显著增加；HEK293细胞高表达AKT后JNK活性明显增加；Wortmanine抑制AKT活性后,消除了高表达AKT对抗Ap诱导的HEK293细胞凋亡。
【结论】
高表达AKT可以有效的对抗AB诱导的细胞毒性,减少细胞凋亡,其机制是通过JNK激酶,促使抗凋亡蛋白Bcl-xL, Bcl-w表达减少和促凋亡Bad和Bax蛋白表达增加来实现的。
第二部分上调PI3K/AKT信号通路对Aβ诱导的tau磷酸化的影响
【背景】
神经原纤维缠结(neurofibrillary tangles, NFTs)是阿尔茨海默病(Alzheimer's disease, AD)的主要病理学特征,NFTs的主要成分是异常过度磷酸化的微管相关蛋白tau,尽管一些研究报道β-淀粉样蛋白(β-amyloid, Aβ)可以通过抑制PI3K/AKT通路激活糖原合成激酶-3(Glycogen synthase kinase 3. GSK3),增加tau磷酸化,但上调AKT表达是否可以保护Aβ诱导的tau磷酸化,仍未见报道。
【目的】
本实验通过在HEK293/tau细胞株中上调PI3K/AKT通路观察神经元中tau磷酸化相关位点的改变及探讨其机制。
【方法】
本实验在HEK293/tau细胞上稳转野生型AKT后,在培养液中加入Aβ1-4220 uM,免疫印迹法检测tau磷酸化位点S396, S214, S404的改变,p-GSK3β-Ser9, m-PP2A-Leu309, PTP1B,表达的变化。
【结果】
(1)在IIEK293/tau细胞中瞬时高表达AKT24小时后,用Aβ处理HEK293/tau细胞,结果显示AKT明显逆转了Aβ诱导的tau多个位点(S396、S214、S404、S198、199、202)磷酸化,总tau含量没有明显改变。(2)转染AKT+Aβ处理组p-GSK3β-Ser9的水平和m-PP2A-Leu309水平比单独Aβ处理组显著升高,而dm-PP2A-Leu309水平明显降低(3)PTPIB表达在AKT+Aβ处理组比单独Aβ处理组明显升高。
【结论】
过表达AKT可以明显的逆转Aβ诱导的tau蛋白磷酸化,其机制是通过PTP1B增加PP2A活性和降低GSK3β活性水平。
Background
Overproduction and accumulation ofβ-amyloid (AP) have been proposed to be an initiating factor of neuron loss in Alzheimer's disease (AD). AKT is a pivotal molecule in regulating neuronal survival; however, it is still not known whether upregulation of AKT can protect the cells from the Aβ-induced apoptosis.
Object
Study on the role of upregulation akt against the Aβ-induced apoptosis in the HEK293 cells.
Methods
We divided the cells into five groups.including control group, AP(1-42) group,vector group,AKTwt group,AKTwt+wortmanine group,and treated the HEK293 cells with 20uM AP(1-42) besides control group.By using AnnexinV- PI double-colouring and flow cytometry,cell viability and cell apoptosis was assayed,the AKTmRNA was detected by RT-PCR. Western blot investigates AKT,caspase-3 bad,bax, Bcl-xL, Bcl-w expression and JNK phosphorylation.
Results
In the present study that upregulation AKT could significantly attenuate the cell apoptosis induced by Aβ(1-42),we also find that the caspase-3,bad,bax expressed in the Aβgroup obviously higher than in the akt group through western blot,moreover the results show that the expression level of Bcl-xL, Bcl-w is significantly decreased in the Aβgroup. Upregulation AKT reduced JNK phosphorylation, and the wortmanine eliminated the effects of overexpressed akt.
Conclusion
these results moreoverly suggest that upregulation AKT attenuate Aβinduced apoptosis mainly through reduced JNK phosphorylation,which regulated the gene balance of acceleration and inhibition apoptosis. the signaling of PI3K/AKT could be a promising therapeutic strategy for arresting AP toxicity in AD patients
Background
Alzheimer's disease is a neurodegenerative disease characterized by the accumulation of beta amyloid into amyloid deposits and by the hyperphosphorylation of the protein tau,leading to neurofibrillary tangles. In addition to tau, abnormally hyperphosphorylated neurofilament is also the protein component of NFTs.β-amyloid peptide could increased the phosphorylation of tau by activating the Gsk-3β. it is still not known whether upregulation of AKT can attenuates the Aβ-induced tau hyperphosphorylation.
Object
Study the changes and mechanism of upregulation akt on the Aβinduced tau phosphorylation.
Methods
After transiently transfected AKTwt in the HEK293 cells, which treated with 20uM Aβ(1-42). Western blot detects the phosphorylation sites of S396, S214, S404, tau-1, tau-5 and pSer9-Gsk3βT-Gsk3β, mL309PP2A, dmLeu309PP2A, PTP1B.
Results
the results shows that:(1) S396,S214,S404 sites obviously decreased in the cells of upregulation AKT. (2) p-GSK3β-Ser9 increased, m-PP2A-Leu309 increased. (3) upregulation AKT increased PTP1B expression
Conclusion
These results indicated that upregulation AKT attenuates the Aβinduced tau phosphorylation.which mainly through increased the activity of PP2A through the signaling of PTP1B.
引文
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