Ostapchenko Valeriy G, Chen Megan, Guzman Monica S, Xie Yu-Feng, Lavine Natalie, Fan Jue, Beraldo Flavio H, Martyn Amanda C, Belrose Jillian C, Mori Yasuo, MacDonald John F, Prado Vania F, Prado Marco A M, Jackson Michael F
Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine, and.
Molecular Medicine, Robarts Research Institute.
J Neurosci. 2015 Nov 11;35(45):15157-69. doi: 10.1523/JNEUROSCI.4081-14.2015.
In Alzheimer's disease, accumulation of soluble oligomers of β-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca(2+)-permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2 is augmented by treatment of cultured neurons with β-amyloid oligomers. Aged APP/PS1 Alzheimer's mouse model showed increased levels of endoplasmic reticulum stress markers, protein disulfide isomerase and phosphorylated eukaryotic initiation factor 2α, as well as decreased levels of the presynaptic marker synaptophysin. Elimination of TRPM2 in APP/PS1 mice corrected these abnormal responses without affecting plaque burden. These effects of TRPM2 seem to be selective for β-amyloid toxicity, as ER stress responses to thapsigargin or tunicamycin in TRPM2(-/-) neurons was identical to that of wild-type neurons. Moreover, reduced microglial activation was observed in TRPM2(-/-)/APP/PS1 hippocampus compared with APP/PS1 mice. In addition, age-dependent spatial memory deficits in APP/PS1 mice were reversed in TRPM2(-/-)/APP/PS1 mice. These results reveal the importance of TRPM2 for β-amyloid neuronal toxicity, suggesting that TRPM2 activity could be potentially targeted to improve outcomes in Alzheimer's disease.
Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress sensing calcium-permeable channel that is thought to contribute to calcium dysregulation associated with neurodegenerative diseases, including Alzheimer's disease. Here we show that oligomeric β-amyloid, the toxic peptide in Alzheimer's disease, facilitates TRPM2 channel activation. In mice designed to model Alzheimer's disease, genetic elimination of TRPM2 normalized deficits in synaptic markers in aged mice. Moreover, the absence of TRPM2 improved age-dependent spatial memory deficits observed in Alzheimer's mice. Our results reveal the importance of TRPM2 for neuronal toxicity and memory impairments in an Alzheimer's mouse model and suggest that TRPM2 could be targeted for the development of therapeutic agents effective in the treatment of dementia.
在阿尔茨海默病中，β-淀粉样肽可溶性寡聚体的积累具有高度毒性，会导致突触活动紊乱和神经元死亡。多项研究将这些影响与氧化应激增加以及钙通透性阳离子通道的异常活动导致的钙失衡联系起来。瞬时受体电位褪黑素2（TRPM2）通道是一种由氧化应激激活的Ca(2+)通透性非选择性阳离子通道，与神经退行性疾病有关，最近还与淀粉样蛋白诱导的毒性有关。在这里，我们表明用β-淀粉样寡聚体处理培养的神经元可增强TRPM2的功能。老年APP/PS1阿尔茨海默病小鼠模型显示内质网应激标志物、蛋白二硫键异构酶和磷酸化真核起始因子2α的水平升高，以及突触前标志物突触素的水平降低。在APP/PS1小鼠中消除TRPM2可纠正这些异常反应，而不影响斑块负荷。TRPM2的这些作用似乎对β-淀粉样毒性具有选择性，因为TRPM2(-/-)神经元对毒胡萝卜素或衣霉素的内质网应激反应与野生型神经元相同。此外，与APP/PS1小鼠相比，在TRPM2(-/-)/APP/PS1海马体中观察到小胶质细胞激活减少。此外，APP/PS1小鼠中与年龄相关的空间记忆缺陷在TRPM2(-/-)/APP/PS1小鼠中得到逆转。这些结果揭示了TRPM2对β-淀粉样蛋白神经元毒性的重要性，表明TRPM2的活性可能是改善阿尔茨海默病预后的潜在靶点。
瞬时受体电位褪黑素2（TRPM2）是一种氧化应激感应钙通透性通道，被认为与包括阿尔茨海默病在内的神经退行性疾病相关的钙调节异常有关。在这里，我们表明阿尔茨海默病中的毒性肽寡聚β-淀粉样蛋白促进TRPM2通道激活。在设计用于模拟阿尔茨海默病的小鼠中，TRPM2的基因消除使老年小鼠突触标志物的缺陷正常化。此外，TRPM2的缺失改善了在阿尔茨海默病小鼠中观察到的与年龄相关的空间记忆缺陷。我们的结果揭示了TRPM2在阿尔茨海默病小鼠模型中对神经元毒性和记忆损伤的重要性，并表明TRPM2可作为开发有效治疗痴呆症药物的靶点。
