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首页> 外文期刊>Molecular brain >Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer’s disease mouse model
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Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer’s disease mouse model

机译：大脑中镁的升高可防止突触丧失并逆转阿尔茨海默氏病小鼠模型的认知缺陷

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Background Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer?s disease, which might underlie memory impairment. Our previous work demonstrates that magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we tested whether elevation of brain magnesium, using a recently developed compound (magnesium-L-threonate, MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic mouse model of Alzheimer?s disease. Results MgT treatment reduced A?-plaque, prevented synapse loss and memory decline in the transgenic mice. Strikingly, MgT treatment was effective even when the treatment was given to the mice at the end-stage of their Alzheimer?s disease-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brain of transgenic mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the transgenic mice, the NMDAR signaling pathway was downregulated, while the BACE1 expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression and reduced sAPP? and ?-CTF in the transgenic mice. At the molecular level, elevation of extracellular magnesium prevented the high A?-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices. Conclusions Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of Alzheimer?s disease, and hence it might have therapeutic potential for treating Alzheimer?s disease.
机译：背景深刻的突触丧失是与阿尔茨海默氏病相关的主要病理标志之一，其可能是记忆障碍的基础。我们以前的工作表明，镁离子是控制突触密度/可塑性的关键因素。在这里，我们测试了使用最近开发的化合物（L-苏糖酸镁，MgT）提高大脑镁的含量是否可以改善ADswe / PS1dE9小鼠（阿尔茨海默氏病的转基因小鼠模型）中的AD样病理和认知缺陷。疾病。结果MgT处理减少了转基因小鼠的Aβ斑块，防止了突触损失和记忆力减退。令人惊讶的是，即使在小鼠阿尔茨海默氏病样病理进展的最后阶段对MgT进行治疗，MgT治疗仍然有效。为了探讨脑镁的升高如何改善转基因小鼠大脑中的AD样病理，我们研究了对APP代谢和突触可塑性/密度相关的信号通路至关重要的分子。在转基因小鼠中，NMDAR信号通路被下调，而BACE1表达被上调。 MgT处理可防止这些信号通路的损伤，稳定BACE1表达并降低sAPP？转基因小鼠中的α-CTF和β-CTF。在分子水平上，细胞外镁的升高通过防止海马切片中钙调磷酸酶的过度活化，阻止了Aβ诱导的突触NMDARs的高降低。结论我们的结果表明，脑镁的升高在阿尔茨海默氏病小鼠模型中具有重要的突触保护作用，因此可能具有治疗阿尔茨海默氏病的治疗潜力。

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