Neuroinflammation as an Integral Component of Neurodegeneration in Parkinson's Disease
https://doi.org/10.52667/2712-9179-2024-4-4-26-33
Abstract
Parkinson's disease (PD) is a progressively advancing neurodegenerative disorder, the pathogenetic mechanisms of which remain poorly understood. The disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. Given the improvement in the quality of medical care provided to the population, it is projected that the total number of patients diagnosed with PD worldwide will rise to 8.7 million by 2030. This review addresses the fundamental aspects of neuroinflammation in the context of PD pathogenesis. There is no doubt that pro-inflammatory immunological mechanisms play a critical role in the onset and progression of the disease. Neuronal-derived cells, such as microglia and astrocytes, act as inducers of neuroinflammation, affecting the permeability of the blood-brain barrier to peripheral immune-competent cells. Furthermore, cytokine patterns of the immune response in PD appear to exist. Potential therapeutic approaches for mitigating neuroinflammation in PD, which have been studied in experimental and in vitro models, are also discussed.
About the Authors
Z. F. Sayfitdinkhuzhaev
Siberian State Medical University
Russian Federation
Russian Federation
Zaynutdinkhuzha F. Sayfitdinkhuzhaev
Tel.: +7-923-408-24-49
634050 Tomsk
N. G. Zhukova
Siberian State Medical University
Russian Federation
Russian Federation
Natalia G. Zhukova
634050 Tomsk
A. N. Baidanova
Siberian State Medical University
Russian Federation
Russian Federation
Alina N. Baidanova
634050 Tomsk
References
1. Dorsey, E.R.; Constantinescu, R.; Thompson, J.P.; et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007, 68(5):384-386. https://doi.org/10.1212/01.wnl.0000254770.21326.28.
2. Liu, B.; Gao, H.M.; Hong, J.S. Parkinson's disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation. Environ Health Perspect. 2003, 111(8):1065-1073. https://doi.org/10.1289/ehp.6361.
3. GBD 2016 Parkinson's Disease Collaborators. Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018, 17(11):939-953. https://doi.org/10.1016/S1474-4422(18)30295-3.
4. Moustafa, A.A.; Chakravarthy, S.; Phillips, J.R.; et al. Motor symptoms in Parkinson's disease: A unified framework. Neurosci Biobehav Rev. 2016, 68:727-740. https://doi.org/10.1016/j.neubiorev.2016.07.010.
5. Schapira, A.H.; Chaudhuri, K.R.; Jenner, P. Non-motor features of Parkinson disease. Nat Rev Neurosci. 2017, 18(8):509. https://doi.org/10.1038/nrn.2017.91.
6. Mahlknecht, P.; Seppi, K.; Poewe, W. The concept of prodromal Parkinson's disease. J Parkinsons Dis. 2015, 5(4):681-697. https://doi.org/10.3233/JPD-150685.
7. Schilder, B.M.; Navarro, E.; Raj, T. Multi-omic insights into Parkinson's Disease: From genetic associations to functional mechanisms. Neurobiol Dis. 2022, 163:105580. https://doi.org/10.1016/j.nbd.2021.105580.
8. Heneka, M.T.; Carson, M.J.; El Khoury, J.; et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015, 14(4):388-405. https://doi.org/10.1016/S1474-4422(15)70016-5.
9. Li, Q.; Barres, B.A. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol. 2018, 18(4):225-242. https://doi.org/10.1038/nri.2017.125.
10. Bachiller, S.; Jiménez-Ferrer, I.; Paulus, A.; et al. Microglia in neurological diseases: a road map to brain-disease dependent-inflammatory response. Front Cell Neurosci. 2018, 12:488. https://doi.org/10.3389/fncel.2018.00488.
11. Ho, M.S. Microglia in Parkinson's disease. Adv Exp Med Biol. 2019, 1175:335-353. https://doi.org/10.1007/978-981-13-9913-8_13.
12. Tan, Y.L.; Yuan, Y.; Tian, L. Microglial regional heterogeneity and its role in the brain. Mol Psychiatry. 2020, 25(2):351-367. https://doi.org/10.1038/s41380-019-0609-8.
13. Esin, R.G.; Safina, D.R.; Hakimova, A.R.; Esin, O.R. Neuroinflammation and neuropathology. Journal of Neurology and Psychiatry named after S.S. Korsakov. 2021, 121(4):107‑112.
14. Hanisch, U.K. Microglia as a source and target of cytokines. Glia. 2002, 40(2):140-155. https://doi.org/10.1002/glia.10161.
15. Colonna, M.; Butovsky, O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017, 35:441-468. https://doi.org/10.1146/annurev-immunol-051116-052358.Sawada
16. M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson's disease. J Neural Transm Suppl. 2006; (70):373-81. https://doi.org/10.1007/978-3-211-45295-0_57.
17. De Lella Ezcurra, A.L.; Chertoff, M.; Ferrari, C.; et al. Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and micro-glia/macrophage activation. Neurobiol Dis. 2010, 37(3):630-640. https://doi.org/10.1016/j.nbd.2009.11.018.
18. Loane, C.; Politis, M. Positron emission tomography neuroimaging in Parkinson's disease. Am J Transl Res. 2011, 3(4):323-341.
19. Cerami, C.; Iaccarino, L.; Perani, D. Molecular imaging of neuroinflammation in neurodegenerative dementias: the role of in vivo PET imaging. Int J Mol Sci. 2017, 18(5):993. https://doi.org/10.3390/ijms18050993.
20. Orr, C.F.; Rowe, D.B.; Mizuno, Y.; et al. A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain. 2005, 128(Pt 11):2665-2674. https://doi.org/10.1093/brain/awh625.
21. Marogianni, C.; Sokratous, M.; Dardiotis, E.; et al. Neurodegeneration and inflammation—an interesting interplay in Parkinson's disease. Int J Mol Sci. 2020, 21(22):8421. https://doi.org/10.3390/ijms21228421.
22. Atik, A.; Stewart, T.; Zhang, J. Alpha-synuclein as a biomarker for Parkinson's disease. Brain Pathol. 2016, 26(3):410-418. https://doi.org/10.1111/bpa.12370.
23. Lindestam Arlehamn, C.S.; Dhanwani, R.; Pham, J.; et al. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson's disease. Nat Commun. 2020, 11(1):1875. https://doi.org/10.1038/s41467-020-15626-w.
24. Mollenhauer, B.; Locascio, J.J.; Schulz-Schaeffer, W.; et al. α-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol. 2011, 10(3):230-240. https://doi.org/10.1016/S1474-4422(11)70014-X.
25. Baba, Y.; Kuroiwa, A.; Uitti, R.J.; Wszolek, Z.K.; Yamada, T. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord. 2005, 11(8):493-498. https://doi.org/10.1016/j.parkreldis.2005.07.005.
26. Brochard, V.; Combadière, B.; Prigent, A.; et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2009, 119(1):182-192. https://doi.org/10.1172/JCI36470.
27. Sulzer, D.; Alcalay, R.N.; Garretti, F.; et al. T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature. 2017, 546(7660):656-661. https://doi.org/10.1038/nature22815.
28. Jiang, S.; Gao, H.; Luo, Q.; Wang, P.; Yang, X. The correlation of lymphocyte subsets, natural killer cell, and Parkinson's disease: a meta-analysis. Neurol Sci. 2017, 38(8):1373-1380. https://doi.org/10.1007/s10072-017-2988-4.
29. Niwa, F.; Kuriyama, N.; Nakagawa, M.; Imanishi, J. Effects of peripheral lymphocyte subpopulations and the clinical correlation with Parkinson's disease. Geriatr Gerontol Int. 2012, 12(1):102-107. https://doi.org/10.1111/j.1447-0594.2011.00740.x.
30. Li, X.; Koudstaal, W.; Fletcher, L.; et al. Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology. Acta Neuropathol. 2019, 137(5):825-836. https://doi.org/10.1007/s00401-019-01974-5.
31. Chiang, H.L.; Lin, C.H. Altered gut microbiome and intestinal pathology in Parkinson's disease. J Mov Disord. 2019, 12(2):67-83. https://doi.org/10.14802/jmd.18067.
32. Singhania, A.; Pham, J.; Dhanwani, R.; et al. The TCR repertoire of α-synuclein-specific T cells in Parkinson's disease is surprisingly diverse. Sci Rep. 2021, 11(1):302. https://doi.org/10.1038/s41598-020-79726-9.
33. Nuytemans, K.; Theuns, J.; Cruts, M.; Van Broeckhoven, C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat. 2010, 31(7):763-780. https://doi.org/10.1002/humu.21277.
34. Shutinoski, B.; Hakimi, M.; Harmsen, I.E.; et al. Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner. Sci Transl Med. 2019, 11(511). https://doi.org/10.1126/scitranslmed.aas9292.
35. Kim, B.; Yang, M.S.; Choi, D.; et al. Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia. PLoS One. 2012, 7(4). https://doi.org/10.1371/journal.pone.0034693.
36. Gardet, A.; Benita, Y.; Li, C.; et al. LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol. 2010, 185(9):5577-85. https://doi.org/10.4049/jimmunol.1000548.
37. Hui, K.Y.; Fernandez-Hernandez, H.; Hu, J.; et al. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med. 2018, 10(423). https://doi.org/10.1126/scitranslmed.aai7795.
38. Pridgeon, J.W.; Olzmann, J.A.; Chin, L.S.; Li, L. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol. 2007, 5(7). https://doi.org/10.1371/journal.pbio.0050172.
39. Kim, J.; Byun, J.W.; Choi, I.; et al. PINK1 deficiency enhances inflammatory cytokine release from acutely prepared brain slices. Exp Neurobiol. 2013, 22(1):38-44. https://doi.org/10.5607/en.2013.22.1.38.
40. Frank-Cannon, T.C.; Tran, T.; Ruhn, K.A.; et al. Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J Neurosci. 2008, 28(43):10825-34. https://doi.org/10.1523/JNEUROSCI.3001-08.2008.
41. Waak, J.; Weber, S.S.; Waldenmaier, A.; et al. Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1. FASEB J. 2009, 23(8):2478-89. https://doi.org/10.1096/fj.08-125153.
42. He, R.; Yan, X.; Guo, J.; et al. Recent advances in biomarkers for Parkinson's disease. Front Aging Neurosci. 2018, 10:305. https://doi.org/10.3389/fnagi.2018.00305.
43. Karpenko, M.N.; Vasilishina, A.A.; Gromova, E.A.; et al. Interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-α levels in CSF and serum in relation to the clinical diversity of Parkinson's disease. Cell Immunol. 2018, 327:77-82. https://doi.org/10.1016/j.cellimm.2018.02.011.
44. Imamura, K.; Hishikawa, N.; Ono, K.; et al. Cytokine production of activated microglia and decrease in neurotrophic factors of neurons in the hippocampus of Lewy body disease brains. Acta Neuropathol. 2005, 109(2):141-50. https://doi.org/10.1007/s00401-004-0919-y.
45. McCoy, M.K.; Martinez, T.N.; Ruhn, K.A.; et al. Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease. J Neurosci. 2006, 26(37):9365-75. https://doi.org/10.1523/JNEUROSCI.1504-06.2006.
46. Elyaman, W.; Khoury, S.J. Th9 cells in the pathogenesis of EAE and multiple sclerosis. Semin Immunopathol. 2017, 39(1):79-87. https://doi.org/10.1007/s00281-016-0604-y.
47. Elyaman, W.; Bradshaw, E.M.; Uyttenhove, C.; et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A. 2009, 106(31):12885-90. https://doi.org/10.1073/pnas.0812530106.
48. Picca, A.; Guerra, F.; Calvani, R.; et al. Mitochondrial signatures in circulating extracellular vesicles of older adults with Parkinson's disease: Results from the EXosomes in PArkiNson's Disease (EXPAND) study. J Clin Med. 2020, 9(2):504. https://doi.org/10.3390/jcm9020504.
49. Deleidi, M.; Gasser, T. The role of inflammation in sporadic and familial Parkinson's disease. Cell Mol Life Sci. 2013, 70(22):4259-73. https://doi.org/10.1007/s00018-013-1352-y.
50. Collins, L.M.; Toulouse, A.; Connor, T.J.; Nolan, Y.M. Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease. Neuropharmacology. 2012, 62(7):2154-68. https://doi.org/10.1016/j.neuropharm.2012.01.028.
51. Tang, P.; Chong, L.; Li, X.; et al. Correlation between serum RANTES levels and the severity of Parkinson's disease. Oxid Med Cell Longev. 2014, 2014:208408. https://doi.org/10.1155/2014/208408.
52. Teema, A.M.; Zaitone, S.A.; Moustafa, Y.M. Ibuprofen or piroxicam protects nigral neurons and delays the development of L-DOPA-induced dyskinesia in rats with experimental Parkinsonism: Influence on angiogenesis. Neuropharmacology. 2016, 107:432.
53. Poly, T.N.; Islam, M.M.R.; Yang, H.C.; Li, Y.J. Non-steroidal anti-inflammatory drugs and risk of Parkinson's disease in the elderly population: a meta-analysis. Eur J Clin Pharmacol. 2019, 75(1):99-108. https://doi.org/10.1007/s00228-018-2561-y.
54. Rees, K.; Stowe, R.; Patel, S.; et al. Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson's disease: evidence from observational studies. Cochrane Database Syst Rev. 2011, (11). https://doi.org/10.1002/14651858.CD008454.pub2.
55. Ferger, B.; Leng, A.; Mura, A.; Hengerer, B.; Feldon, J. Genetic ablation of tumor necrosis factor-alpha (TNF-alpha) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum. J Neurochem. 2004, 89(4):822-33. https://doi.org/10.1111/j.1471-4159.2004.02399.x.
56. Tomás-Camardiel, M.; Rite, I.; Herrera, A.J.; et al. Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood-brain barrier, and damage in the nigral dopaminergic system. Neurobiol Dis. 2004, 16(1):190-201. https://doi.org/10.1016/j.nbd.2004.01.010.
57. Peter, I.; Dubinsky, M.; Bressman, S.; et al. Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 2018, 75(8):939-946. https://doi.org/10.1001/jamaneurol.2018.0605.
58. Jing, H.; Wang, S.; Wang, M.; et al. Isobavachalcone attenuates MPTP-induced Parkinson's disease in mice by inhibition of microglial activation through NF-κB pathway. PLoS One. 2017, 12(1). https://doi.org/10.1371/journal.pone.0169560.
59. Chatterjee, D.; Kordower, J.H. Immunotherapy in Parkinson's disease: Current status and future directions. Neurobiol Dis. 2019, 132:104587. https://doi.org/10.1016/j.nbd.2019.104587.
60. Mandler, M.; Valera, E.; Rockenstein, E.; et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 2014, 127(6):861-79. https://doi.org/10.1007/s00401-014-1256-4.
61. Sanchez-Guajardo, V.; Annibali, A.; Jensen, P.H.; Romero-Ramos, M. α-Synuclein vaccination prevents the accumulation of Parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol. 2013, 72(7):624-45. https://doi.org/10.1097/NEN.0b013e31829768d2.
62. Benner, E.J.; Mosley, R.L.; Destache, C.J.; et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004, 101(25):9435-40. https://doi.org/10.1073/pnas.0400569101.
Review
For citations:
Sayfitdinkhuzhaev Z.F., Zhukova N.G., Baidanova A.N. Neuroinflammation as an Integral Component of Neurodegeneration in Parkinson's Disease. Personalized Psychiatry and Neurology. 2024;4(4):26-33. https://doi.org/10.52667/2712-9179-2024-4-4-26-33
Views:
177
Email this article 