Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1865, Issue 2, Pages 371-377Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2018.11.012
Keywords
Metabolic memory; Neurodegeneration; Glucagon-like peptide-1 receptor agonists; Forkhead box class O
Funding
- National Natural Science Foundation of China, China [81473216, 81673435, 81872850, 81430082]
- Open Project of State Key Laboratory of Natural Medicines, China [SKLNMZZCX201822]
- Double First-Class University Project, China [CPU2018GF08]
- 111 Project from the Ministry of Education of China
- State Administration of Foreign Expert Affairs of China, China [111-2-07]
- PAPD (Priority Academic Program Development of Jiangsu Higher Education Institutions), China
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Metabolic memory, which refers to diabetic stresses that persist after glucose normalization, is considered a major factor in addition to hyperglycaemia for diabetes complications, including dementia. We previously reported that glucagon-like peptide-1 receptor agonist (GLP-1RA) alleviated neuronal injury in diabetes-related dementia models. However, our understanding of the effects and mechanisms of GLP-1RA on metabolic memory induced neurodegeneration are limited. The present study mainly focuses on the mechanisms of action of GLP-IRA on metabolic memory-induced neurotoxicity in vivo and in vitro. Thus, in this study, aiming at mimicking metabolic memory phenomena, in vivo and in vitro models were exposed to high glucose first and then normal glucose. We also used advanced glycation end products, which are key metabolic memory-related factors, to induce neuronal injury in vitro. Based on the models, here, we report that GLP-1RA alleviated neurodegeneration in db/db mice with normalized blood glucose levels controlled with metformin and neuronal damage induced by high glucose treatment followed by withdrawal. GLP-1RA ameliorated metabolic memory-induced amyloid-beta and tau pathologies in vivo and in vitro. Furthermore, the data suggested that GLP-1RA can protect neurons against metabolic memory via Forkhead box class O (FoxO) pathways, and silent information regulator 2 homolog 1-dependent deacetylation and protein kinase B-dependent phosphorylation of FoxO1 were involved in the mechanisms underlying protective effects. This study provides evidence of the beneficial effects of GLP-1RA on neuronal cell metabolic memory, as well as GLP-1 analogues and metformin combination therapy efficiency on cognitive impairment.
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