糖酵解
神经炎症
线粒体
神经退行性变
星形胶质细胞
细胞生物学
厌氧糖酵解
阿尔茨海默病
生物化学
乳酸脱氢酶
生物
化学
炎症
新陈代谢
神经科学
疾病
内科学
医学
酶
免疫学
中枢神经系统
作者
Kelly Ceyzériat,Aurélien M. Badina,Francesco Petrelli,Sylvie Montessuit,Alekos Nicolaides,Stergios Tsartsalis,Armand Savioz,Jean‐Claude Martinou,Benjamin B. Tournier
标识
DOI:10.1016/j.nbd.2024.106623
摘要
Alzheimer's Disease (AD) is characterized by an accumulation of pathologic amyloid-beta (Aβ) and Tau proteins, neuroinflammation, metabolic changes and neuronal death. Reactive astrocytes participate in these pathophysiological processes by releasing pro-inflammatory molecules and recruiting the immune system, which further reinforces inflammation and contributes to neuronal death. Besides these neurotoxic effects, astrocytes can protect neurons by providing them with high amounts of lactate as energy fuel. Astrocytes rely on aerobic glycolysis to generate lactate by reducing pyruvate, the end product of glycolysis, through lactate dehydrogenase. Consequently, limited amounts of pyruvate enter astrocytic mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to be oxidized. The MPC is a heterodimer composed of two subunits MPC1 and MPC2, the function of which in astrocytes has been poorly investigated. Here, we analyzed the role of the MPC in the pathogeny of AD, knowing that a reduction in overall glucose metabolism has been associated with a drop in cognitive performances and an accumulation of Aβ and Tau. We generated 3xTgAD mice in which MPC1 was knocked-out in astrocytes specifically and focused our study on the biochemical hallmarks of the disease, mainly Aβ and neurofibrillary tangle production. We show that inhibition of the MPC before the onset of the disease significantly reduces the quantity of Aβ and Tau aggregates in the brain of 3xTgAD mice, suggesting that acting on astrocytic glucose metabolism early on could hinder the progression of the disease.
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