2. Academic Validation
  3. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease

Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease

  • Nat Med. 2018 Jul;24(7):931-938. doi: 10.1038/s41591-018-0051-5.
Seung Pil Yun 1 2 3,  Tae-In Kam 1 2,  Nikhil Panicker 1 2,  SangMin Kim 1 2,  Yumin Oh 4 5,  Jong-Sung Park 4 5,  Seung-Hwan Kwon 1 2,  Yong Joo Park 4 5,  Senthilkumar S Karuppagounder 1 2 3,  Hyejin Park 1 2,  Sangjune Kim 1 2,  Nayeon Oh 1 2,  Nayoung Alice Kim 1 2,  Saebom Lee 1 2,  Saurav Brahmachari 1 2 3,  Xiaobo Mao 1 2 3,  Jun Hee Lee 6,  Manoj Kumar 1 2,  Daniel An 1 2,  Sung-Ung Kang 1 2,  Yunjong Lee 7,  Kang Choon Lee 8,  Dong Hee Na 9,  Donghoon Kim 1 2 10 11,  Sang Hun Lee 12,  Viktor V Roschke 13,  Shane A Liddelow 14,  Zoltan Mari 2,  Ben A Barres 14,  Valina L Dawson 1 2 3 10 11,  Seulki Lee 15 16,  Ted M Dawson 17 18 19 20 21 22,  Han Seok Ko 23 24 25 26
Affiliations

Affiliations

  • 1 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
  • 4 The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5 The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 6 Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
  • 7 Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea.
  • 8 College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
  • 9 College of Pharmacy, Chung-Ang University, Seoul, South Korea.
  • 10 Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 11 Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 12 Soonchunhyang Medical Science Research Institute, Soonchunhyang University, Seoul Hospital, Seoul, South Korea.
  • 13 Neuraly Inc, Baltimore, MD, USA.
  • 14 Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA, USA.
  • 15 The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 16 The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 17 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 18 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 19 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. [email protected].
  • 20 Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 21 Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 22 Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. [email protected].
  • 23 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 24 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 25 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. [email protected].
  • 26 Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. [email protected].
PMID: 29892066 DOI: 10.1038/s41591-018-0051-5
Abstract

Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer's disease and Parkinson's disease3-13. The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson's disease14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration16. We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson's disease and related neurologic disorders characterized by microglial activation.

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