Centro de Envejecimiento y Regeneración (CARE-UC), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua 2820000, Chile.
Int J Mol Sci. 2022 Aug 5;23(15):8733. doi: 10.3390/ijms23158733.
Impaired cerebral glucose metabolism is an early event that contributes to the pathogenesis of Alzheimer's disease (AD). Importantly, restoring glucose availability by pharmacological agents or genetic manipulation has been shown to protect against Aβ toxicity, ameliorate AD pathology, and increase lifespan. Lithium, a therapeutic agent widely used as a treatment for mood disorders, has been shown to attenuate AD pathology and promote glucose metabolism in skeletal muscle. However, despite its widespread use in neuropsychiatric disorders, lithium's effects on the brain have been poorly characterized. Here we evaluated the effect of lithium on glucose metabolism in hippocampal neurons from wild-type (WT) and APPSwe/PS1ΔE9 (APP/PS1) mice. Our results showed that lithium significantly stimulates glucose uptake and replenishes ATP levels by preferential oxidation of glucose through glycolysis in neurons from WT mice. This increase was also accompanied by a strong increase in glucose transporter 3 (Glut3), the major carrier responsible for glucose uptake in neurons. Similarly, using hippocampal slices from APP-PS1 mice, we demonstrate that lithium increases glucose uptake, glycolytic rate, and the ATP:ADP ratio in a process that also involves the activation of AMPK. Together, our findings indicate that lithium stimulates glucose metabolism and can act as a potential therapeutic agent in AD.
脑内葡萄糖代谢受损是导致阿尔茨海默病（AD）发病的早期事件。重要的是，通过药理学或遗传操作来恢复葡萄糖的可用性，已被证明可以预防 Aβ 毒性、改善 AD 病理、并延长寿命。锂是一种广泛用于治疗情绪障碍的治疗剂，已被证明可以减轻 AD 病理并促进骨骼肌中的葡萄糖代谢。然而，尽管锂在神经精神疾病中的应用广泛，但它对大脑的影响仍未得到充分描述。在这里，我们评估了锂对野生型（WT）和 APPPSwe/PS1ΔE9（APP/PS1）小鼠海马神经元中葡萄糖代谢的影响。我们的结果表明，锂可通过促进 WT 小鼠神经元中的糖酵解作用来显著刺激葡萄糖摄取和通过优先氧化葡萄糖来补充 ATP 水平。这种增加还伴随着葡萄糖转运蛋白 3（Glut3）的强烈增加，Glut3 是神经元中葡萄糖摄取的主要载体。同样，我们使用 APP/PS1 小鼠的海马切片证明，锂可增加葡萄糖摄取、糖酵解率和 ATP:ADP 比，这一过程还涉及 AMPK 的激活。总之，我们的研究结果表明，锂可刺激葡萄糖代谢，可作为 AD 的潜在治疗剂。
