Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease
| Autor: | Martin G. Pomper, Hyunhee Kim, Kang Choon Lee, Eun Ji Park, Dong-Hoon Kim, Seung-Hwan Kwon, Yumin Oh, Valina L. Dawson, Dong Hee Na, Hyejin Park, Jong-Sung Park, Olga Pletnikova, Jae Jin Song, Juan C. Troncoso, Seulki Lee, Aanishaa Jhaldiyal, Saebom Lee, Ted M. Dawson, Han Seok Ko, Tae In Kam |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Agonist medicine.drug_class Mice Transgenic GLP-1 receptor Neuroprotection Glucagon-Like Peptide-1 Receptor Pathology and Forensic Medicine Proinflammatory cytokine Mice Cellular and Molecular Neuroscience Alzheimer Disease medicine Animals Humans Maze Learning Receptor RC346-429 Cells Cultured Neuroinflammation Microglia activation Amyloid beta-Peptides Microglia Chemistry Research Neurodegeneration medicine.disease Peptide Fragments NLY01 GLP-1R agonist Neuroprotective Agents medicine.anatomical_structure nervous system Astrocytes Exenatide Reactive astrocytes Neurology (clinical) Neurology. Diseases of the nervous system Neuroscience Alzheimer’s disease Astrocyte |
| Zdroj: | Acta Neuropathologica Communications, Vol 9, Iss 1, Pp 1-15 (2021) Acta Neuropathologica Communications |
| ISSN: | 2051-5960 |
| Popis: | Alzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R+ microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01180-z. |
| Databáze: | OpenAIRE |
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