Enhanced Glycolysis in Astrocytes Impairs Synaptic Plasticity and Accelerates the Aβ Aggregation in Early Alzheimer's Disease Models

Aberrant energy metabolism in the brain is a common pathological feature in the preclinical Alzheimer's Disease (AD). Glycolysis plays a key role in the early AD according to a large-scale proteomic analysis which reported the early elevations of glycolysis-involved enzymes in AD brain and cerebrospinal fluid. In the physiological condition, lactate, the main metabolites of glycolysis, is required for long-term plasticity and memory formation via astrocyte–neuron lactate shuttle (ANLS). Yet the associations between pathological ANLS caused by enhanced glycolysis and cognitive decline in early AD remains poorly understood. Here, we find that A1-reactive astrocytes, accompanied with enhanced glycolysis, can be induced by Aβ-activated microglia and those process are dependent on the activation of AKT-mTOR-HIF-1α pathway. The lactate boosting generated by enhanced astrocytic glycolysis causes spatial cognition impairment by disrupting synaptic plasticity and accelerating Aβ aggregation. Furthermore, we find rapamycin, the mTOR inhibitor can rescue the impaired spatial memory by inhibiting the glycolysis in the APP/PS1 mice. Collectively, we highlight the pathological significance of ANLS in the early AD pathology and modulating glycolysis might provide new strategies for AD treatment.