1. Academic Validation
  2. GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer's disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway

GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer's disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway

  • Biochem Pharmacol. 2021 Jun;188:114578. doi: 10.1016/j.bcp.2021.114578.
Yunzhen Xie 1 Jiaping Zheng 2 Shiqi Li 1 Huiying Li 1 Yu Zhou 1 Wenrong Zheng 1 Meilian Zhang 3 Libin Liu 2 Zhou Chen 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
  • 2 Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou 350001, China.
  • 3 Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, China; Department of Ultrasound, Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China.
  • 4 School of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, China. Electronic address: chenzhou@fjmu.edu.cn.
Abstract

The glucagon-like peptide-1 (GLP-1) was shown to have neuroprotective effects in Alzheimer's disease (AD). However, the underlying mechanism remains elusive. Astrocytic mitochondrial abnormalities have been revealed to constitute important pathologies. In the present study, we investigated the role of astrocytic mitochondria in the neuroprotective effect of GLP-1 in AD. To this end, 6-month-old 5 × FAD mice were subcutaneously treated with liraglutide, a GLP-1 analogue (25 nmol/kg/qd) for 8 weeks. Liraglutide ameliorated mitochondrial dysfunction and prevented neuronal loss with activation of the cyclic adenosine 3',5'-monophosphate (cAMP)/phosphorylate protein kinase A (PKA) pathway in the brain of 5 × FAD mice. Next, we exposed astrocytes to β-amyloid (Aβ) in vitro and treated them with GLP-1. By activating the cAMP/PKA pathway, GLP-1 increased the phosphorylation of DRP-1 at the s637 site and mitigated mitochondrial fragmentation in Aβ-treated astrocytes. GLP-1 further improved the Aβ-induced energy failure, mitochondrial Reactive Oxygen Species (ROS) overproduction, mitochondrial membrane potential (MMP) collapse, and cell toxicity in astrocytes. Moreover, GLP-1 also promoted the neuronal supportive ability of Aβ-treated astrocytes via the cAMP/PKA pathway. This study revealed a new mechanism behind the neuroprotective effect of GLP-1 in AD.

Keywords

Alzheimer’s disease; Astrocyte; Glucagon-like peptide-1; Mitochondrial dysfunction; cAMP/PKA pathway.

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