Physical exercise protects neurons from energy deficit and improves cognitive function by upregulating astrocytic...

Alzheimer's disease (AD) has been associated with impaired energy metabolism and neuronal mitochondrial dysfunction, which contribute to the development of anxiety-like behaviors and spatial memory deficits. Astrocytes are recognized as a critical source of metabolites for neurons, supporting mitochondrial respiration. Although physical exercise (PE) has shown therapeutic potential in AD models, the molecular mechanisms linking PE to metabolic reprogramming remain elusive. In a 5xFAD mouse model, this study shows that PE increased the expression of solute carrier family 2 member 1 (Slc2a1) and decreased the expression of GFAP in astrocytes. We demonstrate that both PE and the overexpression of astrocytic Slc2a1 alleviated neuronal mitochondria damage and neuron death, shifts astrocytes to an anti-inflammatory phenotype and reduced Aβ accumulation. Conversely, knockdown of Slc2a1 abrogated the protective effects of PE. In vitro, we established an AD glucose-deficiency cell model by incubating cells with 5.5 mM glucose and oligomeric Aβ (oAβ). Our results showed that Slc2a1 overexpression increased lactate secretion in the supernatant of C8-D1A astrocytes. Furthermore, both Slc2a1 overexpression in C8-D1A cells and lactate treatment rescued oAβ-induced mitochondrial oxidative stress and membrane potential alterations in energy-deficient HT22 neurons, thereby enhancing lactate secretion from astrocytes and promoting the lactate shuttle to neuron for energy supply. Collectively, our findings indicate that PE ameliorates anxiety-like behavior and spatial memory deficits, mitigates mitochondrial damage in neurons, and reduces Aβ accumulation in 5xFAD mice through the upregulation of Slc2a1 in astrocytes. Our findings identify Slc2a1 as a pivotal mediator of metabolic support induced by PE and highlights astrocyte-neuron lactate shuttling as a promising therapeutic target for AD.