DMT1抑制物Ebselen对铁诱导β-淀粉样蛋白沉积的抑制作用及分子机制

Recent studies showed that iron metabolism disorder in the brain is one of the main factors leading to the deposition of β-amyloid (Aβ) and the formation of senile plaques in AD. Divalent metal transporter 1 (DMT1) is the main iron ion transmembrane transporter protein. It suggests that DMT1 may be involved in the deposition of Aβ and the formation of senile plaques. But the mechanism is unknown. The previous studies had found: ①DMT1 is significantly increased in the expression of senile plaques in the brains of postmortem AD and APP/PS1 transgenic mice; ②Ebselen could inhibit the function of DMT1 and decrease the level of cellular iron ion; ③Ebselen as an inhibitor of DMT1 could reduce the levels of APP and hydrolytic enzyme. It will be further investigated the mechanism and inhibitory effects of DMT1 inhibitor, Ebselen on the deposition of iron-induced Aβ. In the study, we use APPsw cells and APP/PS1 transgenic mice to analyze the effects of Ebselen on the animal learning and memory, the brain metal ions, the pathway of Aβ generation and the deposition of Aβ in the cell and animal levels. This study will clarify that the role and mechanism of the protective effect of Ebselen on AD neural pathology and create a new strategy for the prevention and treatment in AD.

研究表明，脑铁代谢紊乱是导致阿尔茨海默病(AD)脑内β-淀粉样蛋白(Aβ)沉积形成老年斑的主要因素，二价金属离子转运体(DMT1)是铁离子主要跨膜转运蛋白。由此，推测DMT1参与AD脑内Aβ沉积形成老年斑，但其机制尚未明确。前期研究发现：①DMT1在AD病人尸检脑组织和APP/PS1转基因小鼠脑老年斑内表达显著增高；②Ebselen能抑制DMT1铁转运，降低细胞内铁离子水平；③Ebselen作为DMT1抑制物降低铁诱导的APPsw细胞APP及水解酶蛋白表达水平。为进一步探讨DMT1抑制物Ebselen对铁诱导Aβ沉积的抑制作用机制，本研究拟应用Ebselen处理APPsw细胞和APP/PS1转基因小鼠，在细胞和动物水平分析Ebselen对学习记忆能力、脑内金属离子、Aβ产生通路及Aβ沉积的影响，阐明其通过抑制DMT1铁转运功能，发挥对AD神经病理保护作用机制，为AD的预防和治疗提供新思路。