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.

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

“…Expression of molecules that provide the transport of lactate between astrocytes and neurons, in particular monocarboxylate transporters (MCT), determines the efficiency of the processes of memory formation and learning in the hippocampus, neuronal survival, and functional activity [ 48 ]. Stimulation of astroglial glycolysis by GLP-1 (glucagon-like peptide-1) was recently shown to be effective in supporting neuronal OXPHOS, improving cognitive abilities and suppressing oxidative stress [ 49 ]. ANLS was initially observed in glutamate-stimulated neurons [ 50 ], but some later studies revealed that activated neurons might not be so much dependent on lactate supply from astroglia since they prefer to utilize glucose to support their energetic needs [ 51 ].…”

Role of liraglutide in Alzheimer’s disease pathology

“…Autopsy cohort studies have revealed a limited role of T2D on classical AD neuropathological features (amyloid (Aβ) plaques and tau tangles) [ 4 ]. However, studies in animals show an overall improvement after different administration protocols [ 12 , 13 , 23 , 24 ], including prophylactic [ 23 ] and long-term treatments [ 23 , 25 – 27 ]. Whereas some studies have reported no effects on amyloid pathology [ 28 ], the majority of the results show that LRGT dramatically reduces Aβ plaque size [ 29 ], number [ 19 , 29 ], and burden [ 18 , 23 , 30 – 32 ].…”

“…Likewise, LRGT neuroprotection is mediated by a reduction of neurofilament phosphorylation in 3xTgAD animals [ 12 ]. LRGT also improves synaptic plasticity [ 18 , 34 ], density [ 14 ], structure [ 15 , 27 ], and synapsis number [ 35 ], increasing synaptophysin and PSD-95 levels in AD mice [ 23 , 30 , 35 ] together with increased long-term potentiation and paired-pulse facilitation [ 18 , 30 , 34 , 35 ]. NMDA synapse-associated proteins are restored by LRGT in the hippocampus from hyperhomocysteinemic rats [ 17 ], and cAMP/PKA pathway is also improved [ 14 , 34 ].…”

“…In line with these observations, LRGT also decreases brain oxidative stress, by reducing glucose-6-phosphate dehydrogenase activity, the formation of cortical carbonyl groups, nitrite and 8-hydroxy-2′-deoxyguanosine in 3xTgAD mice [ 13 ]. Similarly, oxidative phosphorylation of cortical astrocytes is reduced in 5xFAD mice [ 27 ] (Fig. 1 ).…”

Regulation of brain aging by neutral sphingomyelinase 2

“…In astrocytes, oxidative phosphorylation in mitochondria is reduced in favor of aerobic glycolysis, which was suggested to diminish oxidative stress and protect neurons (Demetrius and Simon, 2012;Tavallaie et al, 2020;Zheng et al, 2021). Oxidative stress, however, is increased in reactive astrocytes and induces the production of proinflammatory cytokines (Lee et al, 2010).…”