Alteration of brain aerobic glycolysis is often observed early in the course of Alzheimer’s disease (AD). Whether and how such metabolic dysregulation contributes to both synaptic plasticity and behavioral deficits in AD is not known. Here, we show that the astrocytic l-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients. l-serine is the precursor of d-serine, a co-agonist of synaptic NMDA receptors (NMDARs) required for synaptic plasticity. Accordingly, AD mice display a lower occupancy of the NMDAR co-agonist site as well as synaptic and behavioral deficits. Similar deficits are observed following inactivation of the l-serine synthetic pathway in hippocampal astrocytes, supporting the key role of astrocytic l-serine. Supplementation with l-serine in the diet prevents both synaptic and behavioral deficits in AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral l-serine as a ready-to-use therapy for AD.

经常在阿尔茨海默氏病（AD）的早期观察到脑有氧糖酵解的改变。尚不清楚这种代谢失调是否以及如何导致AD中的突触可塑性和行为缺陷。在这里，我们显示了从糖酵解分支出来的星形细胞1-丝氨酸生物合成途径在年轻的AD小鼠和AD患者中受损。1-丝氨酸是d-丝氨酸的前体，d-丝氨酸是突触可塑性所必需的突触NMDA受体（NMDAR）的共激动剂。因此，AD小鼠显示较低的NMDAR激动剂位点占用以及突触和行为缺陷。类似的赤字观察到以下的灭活升-丝氨酸在海马星形胶质细胞中的合成途径，支持星形细胞1-丝氨酸的关键作用。在饮食中补充1-丝氨酸可预防AD小鼠的突触和行为缺陷。我们的研究结果表明，星形胶质细胞的糖酵解控制的认知功能，并建议口服升丝氨酸作为AD准备使用的疗法。