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

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 disease3,4,5,6,7,8,9,10,11,12,13. 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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Fig. 1: α-syn PFF-induced Parkinson’s disease-like pathology is rescued by NLY01.
Fig. 2: NLY01 reduces the pathology in the hA53T α-syn transgenic mice.
Fig. 3: Inhibition of α-syn PFF-induced microglial activation by NLY01.
Fig. 4: Inhibition of α-syn PFF-induced A1 reactive astrocytes by NLY01.

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Acknowledgements

All relevant ethical regulations were followed. This work was supported by grants from the NIH/NINDS NS38377 (H.S.K., V.L.D. and T.M.D.), NIH/NINDS NS082205 and NS098006 (H.S.K.), Maryland Stem Cell Research Foundation 2012-MSCRFE-0059 (H.S.K.), the JPB Foundation (T.M.D.), NIH/National Institute on Aging grant 1K01AG056841-01(X.M.), the American Parkinson Disease Association (APDA) Research Grant Awards (X.M.) and the National Research Foundation of Korea NRF-2016R1D1A1B03934847 (D.H.N.). We acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through their direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Programs M-1 (T.M.D. and V.L.D.), M-2 (T.M.D. and V.L.D.), H-2014 (T.M.D.), M-2014 (H.S.K., T.M.D. and V.L.D.), H-1 (H.S.K.), H-2013 (H.S.K.). T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. We thank Neuraly Inc. for providing NLY01.

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S.P.Y. and T.-I.K. designed the majority of the experiments, performed the experiments, analyzed data and wrote the manuscript. N.P., S.M.K., Y.O., J.-S.P., S.-H.K., S.-U.K. and D.K. performed experiments and data interpretation. Y.J.P. injected NLY01 into mice. S.S.K. performed HPLC analysis. H.P., S.K., N.O., N.A.K., Sa.L., J.H.L., M.K. and D.A. performed sample preparation and helped with experiments. S.B. and X.M. provided and managed mice and PFF, and helped with data interpretation. K.C.L. and D.H.N. provided and made NLY01. V.V.R. performed mouse pharmacokinetic experiments and data analysis. Y.L., S.H.L., S.A.L. and B.A.B. preformed manuscript writing, review and editing. Z.M. provided human postmortem brain samples. V.L.D., Se.L., T.M.D. and H.S.K. supervised the project, formulated the hypothesis, designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Seulki Lee or Ted M. Dawson or Han Seok Ko.

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Competing interests

Z.M., V.L.D., Se.L., T.M.D. and H.S.K are co-founders of Neuraly Inc. and hold ownership equity in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. V.V.R. is the CSO of Neuraly Inc.

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Yun, S.P., Kam, T., Panicker, N. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med 24, 931–938 (2018). https://doi.org/10.1038/s41591-018-0051-5

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