GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer's disease

Astrocytes actively participate in energy metabolism in the brain, and astrocytic aerobic glycolysis disorder is associated with the pathology of Alzheimer's disease (AD). GLP-1 has been shown to improve cognition in AD; however, the mechanism remains unclear. The objectives of this study were to assess GLP-1's glycolytic regulation effects in AD and reveal its neuroprotective mechanisms. The Morris water maze test was used to evaluate the effects of liraglutide (an analog of GLP-1) on the cognition of 4-month-old 5×FAD mice, and a proteomic analysis and Western blotting were used to assess the proteomic profile changes. We constructed an astrocytic model of AD by treating primary astrocytes with Aβ1-42. The levels of NAD+ and lactate were examined, and the oxidative levels were assessed by a Seahorse examination. Astrocyte-neuron co-culture was performed to evaluate the effects of GLP-1 on astrocytes’ neuronal support. GLP-1 improved cognition in 4-month-old 5×FAD mice by enhancing aerobic glycolysis and reducing oxidative phosphorylation (OXPHOS) levels and oxidative stress in the brain. GLP-1 also alleviated Aβ-induced glycolysis declines in astrocytes, which resulted in reduced OXPHOS levels and reactive oxygen species (ROS) production. The mechanism involved the activation of the PI3K/Akt pathway by GLP-1. Elevation in astrocytic glycolysis improved astrocyte cells’ support of neurons and promoted neuronal survival and axon growth. Taken together, we revealed GLP-1's capacity to regulate astrocytic glycolysis, providing mechanistic insight into one of its neuroprotective roles in AD and support for the feasibility of energy regulation treatments for AD. [Display omitted] •GLP-1 mediates a metabolic shift from oxidative phosphorylation to aerobic glycolysis in Alzheimer's disease.•GLP-1's mechanism of action involves activation of the PI3K/Akt pathway.•GLP-1 enhances the supportive ability of astrocytes to neurons by promoting aerobic glycolysis.