| First Author | Ceyz?riat K | Year | 2024 |
| Journal | Neurobiol Dis | Volume | 200 |
| Pages | 106623 | PubMed ID | 39103022 |
| Mgi Jnum | J:366970 | Mgi Id | MGI:7710753 |
| Doi | 10.1016/j.nbd.2024.106623 | Citation | Ceyzeriat K, et al. (2024) Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease. Neurobiol Dis 200:106623 |
| abstractText | Alzheimer's Disease (AD) is characterized by an accumulation of pathologic amyloid-beta (Abeta) 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 Abeta 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 Abeta and neurofibrillary tangle production. We show that inhibition of the MPC before the onset of the disease significantly reduces the quantity of Abeta 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. |
