Aerobic exercise improves cognition in sepsis-associated encephalopathy by enhancing glucose metabolism through astrocytic GLUT1.

Sepsis-associated encephalopathy (SAE) is a common neurological complication of sepsis and a major cause of persistent cognitive impairment in survivors. In recent years, aerobic exercise has attracted increasing attention for its potential roles in improving neural function, regulating systemic metabolism, and preserving cognitive performance; however, whether prior aerobic exercise can mitigate acute sepsis-induced cognitive impairment and its underlying mechanisms remains to be elucidated. Two-sample Mendelian randomization analysis showed that genetically predicted physical activity was associated with a reduced risk of 28-day sepsis mortality. Animal experiments further demonstrated that four weeks of aerobic exercise preconditioning significantly improved cognitive performance in LPS-induced SAE mice, as evidenced by increased spontaneous alternation in the Y-maze and prolonged freezing time in the conditioned fear test. Mechanistically, at day 7 after LPS administration, SAE mice exhibited decreased hippocampal glucose uptake, abnormal glycogen accumulation in the dentate gyrus (DG), and reduced lactate dehydrogenase activity, accompanied by downregulation of astrocytic glucose transporter 1 (GLUT1), decreased expression of synaptic proteins Postsynaptic Density Protein 95 (PSD95) and Synapsin I, and impaired dendritic structure. Aerobic exercise maintained astrocytic GLUT1 expression in the DG and restored hippocampal glucose uptake, thereby alleviating cerebral glucose metabolic disturbances and mitigating synaptic injury. In vitro, LPS stimulation downregulated GLUT1 expression in primary astrocytes and, in an astrocyte-neuron co-culture system, led to reduced neuronal synaptic protein expression through impaired astrocytic support. In vivo overexpression of astrocytic GLUT1 partially recapitulated the protective effects of aerobic exercise on glucose metabolism, synaptic structure, and cognitive function. Collectively, these findings suggest that aerobic exercise attenuates SAE-related cognitive impairment by counteracting the downregulation of astrocytic GLUT1 in the hippocampal DG, thereby maintaining glucose transport, preserving metabolic homeostasis, and protecting synaptic plasticity. These results further support regular aerobic exercise in daily life as a potential non-pharmacological strategy and provide new insights for the prevention and intervention of SAE.