Stimulation of GLP‐1 signaling enhances protein clearance and reduces Aβ‐mediated toxicity in neuronal cells: Molecular and cell biology/protein clearance/recycling. (7th December 2020)

• Record Type: Journal Article
• Authors: Lin, Chih‐Li; Huang, Chien‐Ning; Li, Hsin‐Hua; Chang, Ching‐Chi; Ho, Ying‐Jui; Chiu, Pai‐Yi
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.038285
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Cellular proteostasis failure is proposed to be the major cause of neurodegeneration. The deposition of both extracellular Aβ plaques and intracellular tau‐associated neurofibrillary tangles is central to Alzheimer's disease (AD) pathogenesis. Therefore, development of strategies targeting the removal of misfolded proteins may aid AD treatment. Glucagon‐like peptide‐1 (GLP‐1) is a potent incretin hormone primarily secreted by intestinal L‐cells. It can stimulate pancreatic β‐cells leading to insulin secretion and hence decreasing blood glucose. However, GLP‐1 can also be produced in the brain, and most neuronal cells including neurons and microglia express functional GLP‐1 receptors. Even though it is known for suppressing appetite in hypothalamus, the molecular mechanisms of GLP‐1 signaling are still poorly defined in the other brain regions. Method: In the present study, we aimed at investigating the exact mechanisms underlying GLP‐1‐mediated neuroprotection, and exploring the potential molecular pathways against Aβ‐induced toxicity based on GLP‐1 signaling by using high‐content analysis (HCA) cellomics techniques. Result: We found that GLP‐1 receptor agonist (GLP‐1 RA) liraglutide significantly displays anti‐Aβ neuroprotective effects. These effects were likely associated with an restoration of impaired neuronal insulin signaling. In addition, liraglutide also promoted abnormal protein clearance by upregulating autophagy through the AMP‐activated protein kinase (AMPK) pathway, which subsequently restored neuronal insulin signaling and led to upregulation of nuclear factor erythroid 2‐related factor 2 (NRF2)/heme oxygenase 1 (HO‐1) antioxidant signaling. Furthermore, the efficiency of microglial phagocytosis was also stimulated by liraglutide, and may have a beneficial effect on the clearance of extracellular Aβ. Conclusion: Our results provided the basis for GLP‐1‐based regulatory mechanisms by diminishing Aβ‐related neurotoxicity of neuronal cells. Accordingly, enhanced protein clearance by targeting neuronal GLP‐1 signaling may lead to develop novel therapeutic strategies against AD.