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

Abstract

Objective: 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.

Methods: 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 Aβ_1-42. 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.

Results: 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.

Conclusions: 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.

Keywords: Aerobic glycolysis; Alzheimer's disease; Astrocyte; GLP-1.