Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease

Jong Sung Park, Tae In Kam, Saebom Lee, Hyejin Park, Yumin Oh, Seung Hwan Kwon, Jae Jin Song, Donghoon Kim, Hyunhee Kim, Aanishaa Jhaldiyal, Dong Hee Na, Kang Choon Lee, Eun Ji Park, Martin G. Pomper, Olga Pletnikova, Juan C. Troncoso, Han Seok Ko, Valina L. Dawson, Ted M. Dawson, Seulki Lee

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number78
JournalActa Neuropathologica Communications
Issue number1
StatePublished - Dec 2021


  • Alzheimer’s disease
  • GLP-1 receptor
  • GLP-1R agonist
  • Microglia activation
  • NLY01
  • Reactive astrocytes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease'. Together they form a unique fingerprint.

Cite this