Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease (original) (raw)

References

1. Liddelow, S. A. & Barres, B. A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967 (2017).
   Article PubMed CAS Google Scholar
2. Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
   Article PubMed PubMed Central CAS Google Scholar
3. Athauda, D. & Foltynie, T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: mechanisms of action. Drug Discov. Today 21, 802–818 (2016).
   Article PubMed CAS Google Scholar
4. Aviles-Olmos, I. et al. Exenatide and the treatment of patients with Parkinson’s disease. J. Clin. Invest. 123, 2730–2736 (2013).
   Article PubMed PubMed Central CAS Google Scholar
5. Chen, S. et al. Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation. Neuroscience 256, 137–146 (2014).
   Article PubMed CAS Google Scholar
6. Harkavyi, A. & Whitton, P. S. Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br. J. Pharmacol. 159, 495–501 (2010).
   Article PubMed PubMed Central CAS Google Scholar
7. Li, Y. et al. Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice. J. Neurochem. 135, 1203–1217 (2015).
   Article PubMed PubMed Central CAS Google Scholar
8. Li, Y. et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc. Natl Acad. Sci. USA 106, 1285–1290 (2009).
   Article PubMed Google Scholar
9. Meier, J. J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728–742 (2012).
   Article PubMed CAS Google Scholar
10. Rachmany, L. et al. Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice. Age (Dordr.) 35, 1621–1636 (2013).
    Article CAS Google Scholar
11. Teramoto, S. et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 31, 1696–1705 (2011).
    Article PubMed PubMed Central CAS Google Scholar
12. Tweedie, D. et al. Blast traumatic brain injury-induced cognitive deficits are attenuated by preinjury or postinjury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4. Alzheimers Dement. 12, 34–48 (2016).
    Article PubMed Google Scholar
13. Athauda, D. et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 390, 1664–1675 (2017).
    Article PubMed CAS PubMed Central Google Scholar
14. Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).
    Article PubMed PubMed Central CAS Google Scholar
15. Mao, X. et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).
    Article PubMed PubMed Central CAS Google Scholar
16. Lee, M. K. et al. Human α-synuclein-harboring familial Parkinson’s disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl Acad. Sci. USA 99, 8968–8973 (2002).
    Article PubMed CAS Google Scholar
17. Cabezas, R. et al. Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front. Cell. Neurosci. 8, 211 (2014).
    Article PubMed PubMed Central CAS Google Scholar
18. Gray, M. T. & Woulfe, J. M. Striatal blood–brain barrier permeability in Parkinson’s disease. J. Cereb. Blood Flow Metab. 35, 747–750 (2015).
    Article PubMed PubMed Central CAS Google Scholar
19. Polinski, N. K. et al. Best practices for generating and using alpha-synuclein pre-formed fibrils to model parkinson’s disease in rodents. J. Parkinsons Dis. https://doi.org/10.3233/JPD-171248 (2018).
20. Brahmachari, S. et al. Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. J. Clin. Invest. 126, 2970–2988 (2016).
    Article PubMed PubMed Central Google Scholar
21. Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).
    Article PubMed PubMed Central CAS Google Scholar
22. Kim, C., Lee, H. J., Masliah, E. & Lee, S. J. Non-cell-autonomous neurotoxicity of α-synuclein through microglial Toll-like receptor 2. Exp. Neurobiol. 25, 113–119 (2016).
    Article PubMed PubMed Central CAS Google Scholar
23. Daher, J. P. et al. Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2. Hum. Mol. Genet. 21, 2420–2431 (2012).
    Article PubMed PubMed Central CAS Google Scholar
24. Harms, A. S. et al. Peripheral monocyte entry is required for alpha-synuclein induced inflammation and neurodegeneration in a model of Parkinson disease. Exp. Neurol. 300, 179–187 (2018).
    Article PubMed CAS Google Scholar
25. Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).
    Article PubMed PubMed Central CAS Google Scholar
26. Allen Reish, H. E. & Standaert, D. G. Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. J. Parkinsons Dis. 5, 1–19 (2015).
    PubMed PubMed Central CAS Google Scholar
27. Goncalves, A. et al. Protective effect of a GLP-1 analog on ischemia–reperfusion induced blood–retinal barrier breakdown and inflammation. Invest. Ophthalmol. Vis. Sci. 57, 2584–2592 (2016).
    Article PubMed PubMed Central CAS Google Scholar
28. Gullo, F. et al. Plant polyphenols and exendin-4 prevent hyperactivity and TNF-α release in LPS-treated in vitro neuron/astrocyte/microglial networks. Front. Neurosci. 11, 500 (2017).
    Article PubMed PubMed Central Google Scholar
29. Kim, S., Moon, M. & Park, S. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson’s disease. J. Endocrinol. 202, 431–439 (2009).
    Article PubMed CAS Google Scholar
30. Lee, C.-H. et al. Activation of glucagon-like peptide-1 receptor promotes neuroprotection in experimental autoimmune encephalomyelitis by reducing neuroinflammatory responses. Mol. Neurobiol. 55, 3007–3020 (2018).
    Article PubMed CAS Google Scholar
31. Li, Y. et al. Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. PLoS ONE 7, e32008 (2012).
    Article PubMed PubMed Central CAS Google Scholar
32. Wu, H.-Y., Tang, X.-Q., Liu, H., Mao, X.-F. & Wang, Y.-X. Both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38β/CREB signal pathways mediate exenatide-stimulated expression of M2 microglial markers. J. Neuroimmunol. 316, 17–22 (2018).
    Article PubMed CAS Google Scholar
33. Ventorp, F. et al. Exendin-4 treatment improves LPS-induced depressive-like behavior without affecting pro-inflammatorycytokines. J. Parkinsons Dis. 7, 263–273 (2017).
    Article PubMed PubMed Central CAS Google Scholar
34. Ji, C. et al. A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson’s disease by increasing expression of BNDF. Brain Res. 1634, 1–11 (2016).
    Article PubMed CAS Google Scholar
35. Salcedo, I., Tweedie, D., Li, Y. & Greig, N. H. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br. J. Pharmacol. 166, 1586–1599 (2012).
    Article PubMed PubMed Central CAS Google Scholar
36. Volpicelli-Daley, L. A., Luk, K. C. & Lee, V. M. Addition of exogenous α-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous α-synuclein to Lewy body and Lewy neurite-like aggregates. Nat. Protoc. 9, 2135–2146 (2014).
    Article PubMed PubMed Central CAS Google Scholar
37. Kim, T. H. et al. Mono-PEGylated dimeric exendin-4 as high receptor binding and long-acting conjugates for type 2 anti-diabetes therapeutics. Bioconjug. Chem. 22, 625–632 (2011).
    Article PubMed CAS Google Scholar
38. Kim, T. H. et al. Site-specific PEGylated exendin-4 modified with a high molecular weight trimeric PEG reduces steric hindrance and increases type 2 antidiabetic therapeutic effects. Bioconjug. Chem. 23, 2214–2220 (2012).
    Article PubMed CAS Google Scholar
39. Karuppagounder, S. S. et al. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease. Sci. Rep. 4, 4874 (2014).
    Article PubMed PubMed Central CAS Google Scholar
40. Lee, Y. et al. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat. Neurosci. 16, 1392–1400 (2013).
    Article PubMed PubMed Central CAS Google Scholar
41. Kim, S. et al. GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers. Proc. Natl Acad. Sci. USA 115, 798–803 (2018).
    Article PubMed CAS Google Scholar
42. Panicker, N. et al. Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson’s disease. J. Neurosci. 35, 10058–10077 (2015).
    Article PubMed PubMed Central CAS Google Scholar
43. Andrabi, S. A. et al. Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nat. Med. 17, 692–699 (2011).
    Article PubMed PubMed Central CAS Google Scholar
44. Wang, Y. et al. A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science 354, aad6872 (2016).
    Article PubMed PubMed Central CAS Google Scholar

Download references

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.

Author information

Author notes

1. These authors contributed equally: Seung Pil Yun, Tae-In Kam.

Authors and Affiliations

1. Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
   Seung Pil Yun, Tae-In Kam, Nikhil Panicker, SangMin Kim, Seung-Hwan Kwon, Senthilkumar S. Karuppagounder, Hyejin Park, Sangjune Kim, Nayeon Oh, Nayoung Alice Kim, Saebom Lee, Saurav Brahmachari, Xiaobo Mao, Manoj Kumar, Daniel An, Sung-Ung Kang, Donghoon Kim, Valina L. Dawson, Ted M. Dawson & Han Seok Ko
2. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
   Seung Pil Yun, Tae-In Kam, Nikhil Panicker, SangMin Kim, Seung-Hwan Kwon, Senthilkumar S. Karuppagounder, Hyejin Park, Sangjune Kim, Nayeon Oh, Nayoung Alice Kim, Saebom Lee, Saurav Brahmachari, Xiaobo Mao, Manoj Kumar, Daniel An, Sung-Ung Kang, Donghoon Kim, Zoltan Mari, Valina L. Dawson, Ted M. Dawson & Han Seok Ko
3. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA
   Seung Pil Yun, Senthilkumar S. Karuppagounder, Saurav Brahmachari, Xiaobo Mao, Valina L. Dawson, Ted M. Dawson & Han Seok Ko
4. The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
   Yumin Oh, Jong-Sung Park, Yong Joo Park & Seulki Lee
5. The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
   Yumin Oh, Jong-Sung Park, Yong Joo Park & Seulki Lee
6. Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
   Jun Hee Lee
7. Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea
   Yunjong Lee
8. College of Pharmacy, Sungkyunkwan University, Suwon, South Korea
   Kang Choon Lee
9. College of Pharmacy, Chung-Ang University, Seoul, South Korea
   Dong Hee Na
10. Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Donghoon Kim & Valina L. Dawson
11. Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Donghoon Kim, Valina L. Dawson & Ted M. Dawson
12. Soonchunhyang Medical Science Research Institute, Soonchunhyang University, Seoul Hospital, Seoul, South Korea
    Sang Hun Lee
13. Neuraly Inc, Baltimore, MD, USA
    Viktor V. Roschke
14. Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA, USA
    Shane A. Liddelow & Ben A. Barres
15. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Ted M. Dawson
16. Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA
    Ted M. Dawson & Han Seok Ko

Authors

1. Seung Pil Yun
   You can also search for this author inPubMed Google Scholar
2. Tae-In Kam
   You can also search for this author inPubMed Google Scholar
3. Nikhil Panicker
   You can also search for this author inPubMed Google Scholar
4. SangMin Kim
   You can also search for this author inPubMed Google Scholar
5. Yumin Oh
   You can also search for this author inPubMed Google Scholar
6. Jong-Sung Park
   You can also search for this author inPubMed Google Scholar
7. Seung-Hwan Kwon
   You can also search for this author inPubMed Google Scholar
8. Yong Joo Park
   You can also search for this author inPubMed Google Scholar
9. Senthilkumar S. Karuppagounder
   You can also search for this author inPubMed Google Scholar
10. Hyejin Park
    You can also search for this author inPubMed Google Scholar
11. Sangjune Kim
    You can also search for this author inPubMed Google Scholar
12. Nayeon Oh
    You can also search for this author inPubMed Google Scholar
13. Nayoung Alice Kim
    You can also search for this author inPubMed Google Scholar
14. Saebom Lee
    You can also search for this author inPubMed Google Scholar
15. Saurav Brahmachari
    You can also search for this author inPubMed Google Scholar
16. Xiaobo Mao
    You can also search for this author inPubMed Google Scholar
17. Jun Hee Lee
    You can also search for this author inPubMed Google Scholar
18. Manoj Kumar
    You can also search for this author inPubMed Google Scholar
19. Daniel An
    You can also search for this author inPubMed Google Scholar
20. Sung-Ung Kang
    You can also search for this author inPubMed Google Scholar
21. Yunjong Lee
    You can also search for this author inPubMed Google Scholar
22. Kang Choon Lee
    You can also search for this author inPubMed Google Scholar
23. Dong Hee Na
    You can also search for this author inPubMed Google Scholar
24. Donghoon Kim
    You can also search for this author inPubMed Google Scholar
25. Sang Hun Lee
    You can also search for this author inPubMed Google Scholar
26. Viktor V. Roschke
    You can also search for this author inPubMed Google Scholar
27. Shane A. Liddelow
    You can also search for this author inPubMed Google Scholar
28. Zoltan Mari
    You can also search for this author inPubMed Google Scholar
29. Ben A. Barres
    You can also search for this author inPubMed Google Scholar
30. Valina L. Dawson
    You can also search for this author inPubMed Google Scholar
31. Seulki Lee
    You can also search for this author inPubMed Google Scholar
32. Ted M. Dawson
    You can also search for this author inPubMed Google Scholar
33. Han Seok Ko
    You can also search for this author inPubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence toSeulki Lee, Ted M. Dawson or Han Seok Ko.

Ethics declarations

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.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

About this article

Cite this article

Yun, S.P., Kam, TI., 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

Download citation

• Received: 20 July 2017
• Accepted: 06 April 2018
• Published: 11 June 2018
• Issue Date: July 2018
• DOI: https://doi.org/10.1038/s41591-018-0051-5