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Nat Med. 2018 Jul;24(7):931-938. doi: 10.1038/s41591-018-0051-5. Epub 2018 Jun 11.

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

Yun SP1,2,3, Kam TI1,2, Panicker N1,2, Kim S1,2, Oh Y4,5, Park JS4,5, Kwon SH1,2, Park YJ4,5, Karuppagounder SS1,2,3, Park H1,2, Kim S1,2, Oh N1,2, Kim NA1,2, Lee S1,2, Brahmachari S1,2,3, Mao X1,2,3, Lee JH6, Kumar M1,2, An D1,2, Kang SU1,2, Lee Y7, Lee KC8, Na DH9, Kim D1,2,10,11, Lee SH12, Roschke VV13, Liddelow SA14, Mari Z2, Barres BA14, Dawson VL1,2,3,10,11, Lee S15,16, Dawson TM17,18,19,20,21,22, Ko HS23,24,25,26.

Author information

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. slee343@jhmi.edu.
16
The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. slee343@jhmi.edu.
17
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu.
18
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu.
19
Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. tdawson@jhmi.edu.
20
Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu.
21
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu.
22
Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. tdawson@jhmi.edu.
23
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. hko3@jhmi.edu.
24
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. hko3@jhmi.edu.
25
Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. hko3@jhmi.edu.
26
Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. hko3@jhmi.edu.

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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