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

阿尔茨海默病(AD)发病的分子和细胞机制尚不完全清楚 明白了。阿尔茨海默病的异质性和多因素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，如淀粉样蛋白、tau、ApoE、TREM2、生物金属 (Ca2+、Mg2+、Cu2+等)还有其他人。本研究的目的是探索镁离子在神经细胞中的潜在作用。 类AD病理条件下的保护及其潜在的分子机制。其基本原理是 1)镁离子缺乏与衰老和AD病理有关，2)脑内镁离子浓度升高可增强学习能力 和记忆，减少神经炎症，保护AD动物的认知功能和突触可塑性 模特们。先前的研究表明，阿尔茨海默病患者的大脑和血清镁离子水平显著低于 在年龄匹配的正常受试者中。此外，镁离子升高可增强老年大鼠的学习记忆能力。 预防APP/PS1 AD小鼠和链脲佐菌素诱导的突触丢失和逆转认知障碍 散发性AD大鼠模型，以及减轻神经炎性脑损伤和APP/PS1 AD模型。根据…… 这些发现，大脑中镁离子的动态平衡失调被认为与阿尔茨海默病的进展有关。在……里面 此外，镁离子本身是一种天然的抗氧化剂，是钙离子的拮抗剂，也是ATP的重要辅因子。 酸和600多种酶系统。因此，总而言之，假设是镁离子通过服务于 作为一种抗氧化剂，可以减少氧化应激、炎症和突触丢失。目标1是检查疗效和 镁离子减轻氧化应激和神经炎症的机制。目标2是检查疗效和 镁离子抑制A-β诱导的突触丢失和功能障碍的机制第一，镁离子的作用机制 进入细胞并减少β在体外诱导的氧化应激和炎症将被阐明并遵循 通过在AD动物模型上验证其对氧化应激和炎症的抑制作用。接下来， 镁离子保护神经元免受β诱导的突触丢失和功能障碍的机制以及β- 体外诱导tau蛋白过度磷酸化和线粒体碎裂。最后，镁离子对突触的作用 AD动物模型的可塑性和认知功能障碍的改善将得到验证。

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.