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首页> 美国卫生研究院文献>Aging Cell >Photobiomodulation suppresses JNK3 by activation of ERK/MKP7 to attenuate AMPA receptor endocytosis in Alzheimers disease
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Photobiomodulation suppresses JNK3 by activation of ERK/MKP7 to attenuate AMPA receptor endocytosis in Alzheimers disease

机译：光致调节通过激活ERK / MKP7来抑制JNK3以衰减阿尔茨海默病患者的AMPA受体内吞作用

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Alzheimer's disease (AD), a severe age‐related neurodegenerative disorder, lacks effective therapeutic methods at present. Physical approaches such as gamma frequency light flicker that can effectively reduce amyloid load have been reported recently. Our previous research showed that a physical method named photobiomodulation (PBM) therapy rescues Aβ‐induced dendritic atrophy in vitro. However, it remains to be further investigated the mechanism by which PBM affects AD‐related multiple pathological features to improve learning and memory deficits. Here, we found that PBM attenuated Aβ‐induced synaptic dysfunction and neuronal death through MKP7‐dependent suppression of JNK3, a brain‐specific JNK isoform related to neurodegeneration. The results showed PBM‐attenuated amyloid load, AMPA receptor endocytosis, dendrite injury, and inflammatory responses, thereby rescuing memory deficits in APP/PS1 mice. We noted JNK3 phosphorylation was dramatically decreased after PBM treatment in vivo and in vitro. Mechanistically, PBM activated ERK, which subsequently phosphorylated and stabilized MKP7, resulting in JNK3 inactivation. Furthermore, activation of ERK/MKP7 signaling by PBM increased the level of AMPA receptor subunit GluR 1 phosphorylation and attenuated AMPA receptor endocytosis in an AD pathological model. Collectively, these data demonstrated that PBM has potential therapeutic value in reducing multiple pathological features associated with AD, which is achieved by regulating JNK3, thus providing a noninvasive, and drug‐free therapeutic strategy to impede AD progression.
机译：Alzheimer的疾病（AD）是一种严重的年龄相关的神经退行性疾病，目前缺乏有效的治疗方法。最近已经报道了可以有效地减少淀粉样蛋白载荷的伽马频率光闪烁等物理方法。我们以前的研究表明，一种名为PhotoBioModulation（PBM）治疗的物理方法拯救了体外Aβ诱导的树突萎缩。然而，仍有待进一步调查PBM影响广告相关多种病理特征以改善学习和记忆缺陷的机制。在这里，我们发现PBM通过MKP7依赖性抑制JNK3，与神经变性有关的脑特异性JNK同种型，降低了Aβ诱导的突触功能障碍和神经元死亡。结果表明，PBM减毒的淀粉样蛋白载荷，AMPA受体内吞作用，枝晶损伤和炎症反应，从而抵押APP / PS1小鼠中的记忆缺陷。我们注意到在体内和体外PBM处理后JNK3磷酸化显着降低。机械上，PBM活化ERK，随后磷酸化和稳定的MKP7，导致JNK3失活。此外，通过PBM激活ERK / MKP7信号传导增加AMPA受体亚基Glur1磷酸化水平并在AD病理模型中衰减AMPA受体内吞作用。总的来说，这些数据证明，PBM具有降低与AD相关的多种病理特征的潜在治疗价值，这通过调节JNK3来实现非侵入性和无毒的治疗策略来阻碍广告进展。

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