Molecular Mechanism and Functional Role of Magnesium in Neuroinflammation in Alzheimer's Disease

阿尔茨海默病（Alzheimer's disease，AD）发病的分子和细胞机制尚不完全清楚 明白AD的异质性和多因素性的潜在危险因素可能包括遗传 背景、环境、生活方式和关键分子的状态，即淀粉样蛋白、tau蛋白、ApoE、TREM 2、生物金属 (Ca2+、Mg 2+、Cu 2+等）等人本研究的目的是探讨Mg ~（2+）对神经细胞的作用， 在AD样病理条件下的保护作用和潜在的分子机制。其基本原理是 1）Mg 2+缺乏与衰老和AD病理学相关，2）脑Mg 2+升高增强学习能力 和记忆，减少神经炎症，并保护AD动物的认知功能和突触可塑性 模型先前的研究显示，AD患者的脑和血清Mg 2+水平显著低于 年龄匹配的正常受试者。此外，Mg 2+升高增强老年大鼠的学习和记忆， 在APP/PS1 AD小鼠和链脲佐菌素诱导的AD小鼠中， 散发性AD大鼠模型，以及减少脑损伤和APP/PS1 AD模型中的神经炎症。鉴于 根据这些发现，认为脑中Mg 2+的动态平衡障碍与AD的进展有关。在 此外，Mg ~（2+）本身也是一种天然的抗氧化剂，是Ca ~（2+）的拮抗剂，是ATP、核酸等必需的辅助因子， 酸和超过600种酶系统。因此，总的来说，假设是Mg 2+通过服务于 作为一种抗氧化剂，以减少氧化应激，炎症和突触损失。目的1是检查疗效， Mg 2+减轻氧化应激和神经炎症的机制。目的2是检查疗效， Mg ~（2+）抑制Aβ诱导的突触丢失和功能障碍的机制。第一，Mg 2 + 进入细胞并减少Aβ诱导的体外氧化应激和炎症将得到阐明和遵循 通过在AD动物模型中验证其对氧化应激和炎症抑制的功效。接下来 Mg 2+如何保护神经元免受Aβ诱导的突触丢失和功能障碍的机制，以及Aβ- 诱导tau蛋白过度磷酸化和线粒体片段化。最后，研究了Mg ~（2+）对突触的影响。 将验证AD动物模型中的可塑性和认知缺陷改善。

The molecular and cellular mechanism involved in the etiology of Alzheimer’s disease (AD) is still not fully understood. The risk factors underlying the heterogeneity and multifactorial nature of AD may include genetic background, environment, life styles, and the status of key molecules, i.e. amyloid, tau, ApoE, TREM2, biometals (Ca2+, Mg2+, Cu2+, etc.) and others. The goal of this study is to explore the potential role of Mg2+ in neuronal cell protection under AD-like pathological conditions and the underlying molecular mechanisms. The rationale is that 1) Mg2+-deficiency is correlated to aging and AD pathology, and 2) elevated brain Mg2+ enhances learning and memory, reduces neuroinflammation, and protects cognitive functions and synaptic plasticity in AD animal models. Prior studies revealed that brain and serum Mg2+ levels are significantly lower in patients with AD than in age-matched normal subjects. Moreover, Mg2+ elevation enhanced learning and memory in aged rats, prevented synaptic loss and reversed cognitive deficits in APP/PS1 AD mice and streptozotocin-induced sporadic AD rat model, as well as reduced neuroinflammation in brain injury and APP/PS1 AD model. In light of these findings, dyshomeostasis of Mg2+ in the brain is believed to be involved in the progression of AD. In addition, Mg2+ itself is a nature antioxidant, an antagonist of Ca2+, and an essential cofactor for ATP, nucleic acids and over 600 enzyme systems. Thus collectively, the hypothesis is that Mg2+ protects neurons by serving as an antioxidant to reduce oxidative stress, inflammation, and synaptic loss. Aim 1 is to examine efficacy and mechanism of Mg2+ on reducing oxidative stress and neuroinflammation. Aim 2 is to examine efficacy and mechanism of Mg2+ on inhibiting Aβ-induced synaptic loss and dysfunction. First, the mechanisms of how Mg2+ enters the cells and reduces Aβ-induced oxidative stress and inflammation in vitro will be elucidated and followed by validation of its efficacy on oxidative stress & inflammation suppression in AD animal model. Next, the mechanisms of how Mg2+ protects neurons from Aβ-induced synaptic loss and dysfunction, as well as Aβ- induced tau hyperphosphorylation and mitochondrial fragmentation in vitro. Last, the efficacy of Mg2+ on synaptic plasticity and cognitive deficits amelioration in AD animal model will be validated.