Aβ42通过甲酰肽样受体-1造成神经干/前体细胞老化

Up to now, cell replacement therapy obtained limited benefits in alzheimer's disease(AD). The local hostile microenviroment of brain is the key element for the low efficiency of nerve regeneration. Based on our preliminary results, we found that the failure of adult neurogenesis can be divided into different stages in the process of AD development. Therefore, we hypothesize that amyloid β1-42 causes the failure of neurogenesis through formyl peptide like receptor-1. Firstly, amyloid β1-42 binding to formyl peptide like receptor-1 induces the proliferation and migration of neural stem/progenitor cells. After long-term interaction with amyloid β1-42, the expression of G protein-coupled receptor kinase (GRK) 6 and 2 are sequentially upregulated and cause heterologous desensitization of chemokine receptors in neural stem/progenitor cells. The migratory capacity of neural stem /progenitor cells decrease correspondently. GRK2 upregulation has been regarded as primary hallmark of mitochandria lesion. Overexpression of GRK2 also inhibits the expression of insulin receptors in neural stem/progenitor cells, which worsens the defects in energy metabolism and produces reactive oxygen species(ROS). As the prolonged interaction with amyloid β1-42 or the increasing of amyloid β1-42 concentration, ROS further upregulate caveolin-1 expression by stimulating oxidative stess response elements of caveolin-1 promoter in neural stem /progenitor cells. Caveolin-1 acts as a scaffolding protein that concentrates and functionally regulates signaling molecules. Although overexpression of caveolin-1 can resist to exogenous stress, it may also cause cell cycle irreversible arrest and desensitization to exogenous growth factors by inhibiting MEK-ERK1/2 signal transduction in neural stem/progenitor cells. The development of premature senescence after overexpression of caveolin-1 may be responsible for the failure of neural regeneration in alzheimer's disease.Therefore, effective interference steps should be made according to the stages of neurodegeneration in alzheimer's disease, which may reverse the inhibitory effects of amyloid β1-42 on neurogenisis. The confirmation of the hypothesis about how amyloid causes the failure of neurogensis may help find new therapeutic targets in alzheimer's disease. The effective interference according to the stages of neurodegeneration may fasten the application of cell replacement therapy in neurodegeneration.

单纯补充神经干/前体细胞对阿尔茨海默病(AD)疗效不理想，局部不良微环境成为神经再生效率低的关键。我们前期工作发现：在AD发生、发展过程中，脑内神经干/前体细胞再生障碍存在阶段性变化。为此，我们提出以下假说：低浓度Aβ持续性激活神经干/前体细胞甲酰肽样受体-1，细胞内GRK6、GRK2表达量显著增加，造成细胞趋化因子受体和胰岛素受体脱敏。细胞迁移能力下降，伴能量代谢障碍，活性氧产量增加。随Aβ作用时间延长或剂量增加，活性氧使神经干/前体细胞表面的caveolin-1表达上调。长期高表达caveolin-1虽然可以抑制细胞对外界促凋亡信号的敏感性，但也抑制与细胞增殖有关的信号转导途径，造成神经干/前体细胞对外源性生长因子刺激不敏感，细胞周期不可逆性停滞，衰老加速,并最终死亡。该假说的证实将有助于人们找到新的靶点，针对性地干预神经再生失败，加快神经干/前体细胞在神经退行性疾病中地应用。

单纯补充神经干/前体细胞对阿尔茨海默病(AD)疗效不理想，局部不良微环境成为神经再生效率低的关键。我们工作发现：在AD发生、发展过程中，脑内神经干/前体细胞再生障碍存在阶段性变化。低浓度Aβ可激活神经干/前体细胞甲酰肽样受体-1，早期可促进神经干细胞迁移及增殖，持续性低浓度Aβ可导致细胞内GRK6、GRK2表达量依次增高，造成细胞趋化因子受体和胰岛素受体脱敏，细胞迁移能力下降，伴能量代谢障碍，活性氧产量增加，激活p38通路，造成神经干细胞少量凋亡，抗氧化剂可以部分逆转GRK2表达增加，抑制Aβ造成的神经干细胞增殖。随Aβ作用时间延长或剂量增加，活性氧使神经干/前体细胞表面的caveolin-1表达上调。长期高表达caveolin-1虽然可以抑制细胞对外界促凋亡信号的敏感性，但也抑制与细胞增殖有关的信号转导途径，造成神经干/前体细胞对外源性生长因子刺激不敏感，细胞周期不可逆性停滞，衰老加速,并最终死亡，抗氧化剂有助于逆转神经干细胞老化，甲酰肽样受体-1拮抗剂早期应用仅可部分逆转神经干细胞老化，提示Aβ可通过神经干细胞上多个受体造成神经干细胞老化。大麻素受体拮抗剂可作为自噬调节剂可以抑制胰岛素后信号异常及神经干细胞衰老。此研究有助于人们找到新的靶点，针对性地干预神经再生失败，加快神经干/前体细胞在神经退行性疾病中地应用。

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