RESEARCH PAPER
Cerebral administration of alpha-synuclein monomers modulates inflammatory reaction in nigro-striatal system
 
More details
Hide details
1
Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Poland
2
Gladstone Institutes of Neurological Disease, United States
3
Department of Neurology, Institute of Psychiatry and Neurology, Poland
CORRESPONDING AUTHOR
Ilona Joniec-Maciejak   

Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Banacha 1B, 02-097, Warsaw, Poland
 
J Pre Clin Clin Res. 2019;13(1):26–36
KEYWORDS
TOPICS
ABSTRACT
Introduction:
It has been established that changes in the levels of a-synuclein (ASN) are associated with Parkinson’s disease (PD). The progression of PD is characterized by immune response and inflammation, especially the activation of the microglia. Activated microglia cells release potentially cytotoxic substances, such as pro-inflammatory cytokines, caspases as well as neuroprotective molecules such as neurotrophins.

Objective:
We examined the potential role of recombinant ASN monomers as a major pathogenic factor causing inflammatory responses in the central nervous system.

Methods:
Mice were bilaterally infused with human ASN monomers into the striatum (ST) or substantia nigra pars compacta (SNpc) (single treatment was 4μg/structure, 8μg per brain) and decapitated after 1, 4 or 12 weeks post injection. The changes in the level of neurotrophins, receptor for neurotrophins, marker of microglia and adhesion molecules in ST were evaluated using Real-Time PCR. The analysis of morphological changes of T lymphocytes was performed by immunohistochemical staining.

Results:
In our study, we reported a CD4+ T-cell infiltration to the CNS following ASN delivery to ST or SNpc. We observed a slight effect of ASN on the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). The present study demonstrated an increase in the expression of the glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and receptors of nerve growth factor (NGF) – TrkA, receptor of BDNF – TrkB, receptor of NT-3 – TrkC, following the administration of ASN into ST.

 
REFERENCES (59)
1.
Halliday GM,Stevens CH. Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord. 2011; 26: 6–17.
 
2.
Sanchez-Guajardo V, Tentillier N, Romero-Ramos M. The relation between α-synuclein and microglia in Parkinson’s disease: Recent developments. Neuroscience. 2015; 302: 47–58.
 
3.
Sznejder-Pacholek A, Joniec-Maciejak I, Wawer A, Ciesielska A, Mirowska-Guzel D. The effect of alpha-synuclein on gliosis and IL-1alpha, TNFalpha, IFNgamma, TGFbeta expression in murine brain. Pharmacol Rep. 2017; 69: 242–251.
 
4.
Gardai SJ, Mao W, Schule B, Babcock M, Schoebel S, Lorenzana C, et al. Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson’s disease. PLoS One. 2013; 8: e71634.
 
5.
Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, et al. Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem. 2008; 104: 1504–25.
 
6.
Beraud D, Hathaway HA, Trecki J, Chasovskikh S, Johnson DA, Johnson JA, et al. Microglial activation and antioxidant responses induced by the Parkinson’s disease protein alpha-synuclein. J Neuroimmune Pharmacol. 2013; 8: 94–117.
 
7.
Sacino AN, Brooks M, McKinney AB, Thomas MA, Shaw G, Golde TE, et al. Brain Injection of alpha-Synuclein Induces Multiple Proteinopathies, Gliosis, and a Neuronal Injury Marker. J Neurosci. 2014; 34: 12368–78.
 
8.
Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993; 260: 1130–2.
 
9.
Cheng FC, Ni DR, Wu MC, Kuo JS, Chia LG. Glial cell line-derived neurotrophic factor protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in C57BL/6 mice. Neurosci Lett. 1998; 252: 87–90.
 
10.
Kells AP, Eberling J, Su X, Pivirotto P, Bringas J, Hadaczek P, et al. Regeneration of the MPTP-lesioned dopaminergic system after convection-enhanced delivery of AAV2-GDNF. Journal of Neuroscience. 2010; 30: 9567–9577.
 
11.
Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003; 9: 589–95.
 
12.
Ciesielska A, Mittermeyer G, Hadaczek P, Kells AP, Forsayeth J, Bankiewicz KS. Anterograde Axonal Transport of AAV2-GDNF in Rat Basal Ganglia. Molecular Therapy. 2011; 19: 922–927.
 
13.
Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP, et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature. 1991; 350: 230–2.
 
14.
Alderson RF, Alterman AL, Barde YA, Lindsay RM. Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron. 1990; 5: 297–306.
 
15.
Bekinschtein P, Cammarota M, Izquierdo I, Medina JH. BDNF and memory formation and storage. Neuroscientist. 2008; 14: 147–56.
 
16.
Alonso M, Vianna MR, Depino AM, Mello e Souza T, Pereira P, Szapiro G, et al. BDNF-triggered events in the rat hippocampus are required for both short-and long-term memory formation. Hippocampus. 2002; 12: 551–60.
 
17.
Weinstein G, Beiser AS, Choi SH, Preis SR, Chen TC, Vorgas D, et al. Serum brain-derived neurotrophic factor and the risk for dementia: the Framingham Heart Study. JAMA Neurol. 2014; 71: 55–61.
 
18.
Diniz BS,Teixeira AL. Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond. Neuromolecular Med. 2011; 13: 217–22.
 
19.
Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci. 2001; 24: 1217–81.
 
20.
Nico B, Mangieri D, De Luca A, Corsi P, Benagiano V, Tamma R, et al. Nerve growth factor and its receptors TrkA and p75 are upregulated in the brain of mdx dystrophic mouse. Neuroscience. 2009; 161: 1057–1066.
 
21.
Kaplan DR,Miller FD. Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol. 1997; 9: 213–21.
 
22.
Santos NAG, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, Queiroz RHC, et al. The neuroprotection of cannabidiol against MPP+-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson’s disease. Toxicology in Vitro. 2015; 30: 231–240.
 
23.
Lau YS, Patki G, Das-Panja K, Le WD, Ahmad SO. Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration. Eur J Neurosci. 2011; 33: 1264–74.
 
24.
Tuon T, Valvassori SS, Dal Pont GC, Paganini CS, Pozzi BG, Luciano TF, et al. Physical training prevents depressive symptoms and a decrease in brain-derived neurotrophic factor in Parkinson’s disease. Brain Res Bull. 2014; 108: 106–12.
 
25.
Sobue G, Yamamoto M, Doyu M, Li M, Yasuda T, Mitsuma T. Expression of mRNAs for neurotrophins (NGF, BDNF, and NT-3) and their receptors (p75NGFR, trk, trkB, and trkC) in human peripheral neuropathies. Neurochem Res. 1998; 23: 821–9.
 
26.
Besser M,Wank R. Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol. 1999; 162: 6303–6.
 
27.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003; 112: 257–69.
 
28.
Hudson J, Granholm AC, Gerhardt GA, Henry MA, Hoffman A, Biddle P, et al. Glial cell line-derived neurotrophic factor augments midbrain dopaminergic circuits in vivo. Brain Res Bull. 1995; 36: 425–32.
 
29.
Cai J, Hua F, Yuan L, Tang W, Lu J, Yu S, et al. Potential Therapeutic Effects of Neurotrophins for Acute and Chronic Neurological Diseases. Biomed Res Int. 2014; 2014: 601084.
 
30.
Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med. 1999; 189: 865–70.
 
31.
Heese K, Fiebich BL, Bauer J, Otten U. NF-kappaB modulates lipopolysaccharide-induced microglial nerve growth factor expression. Glia. 1998; 22: 401–7.
 
32.
Imamura K, Hishikawa N, Ono K, Suzuki H, Sawada M, Nagatsu T, 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: 141–50.
 
33.
McGeer PL,McGeer EG. Glial reactions in Parkinson’s disease. Mov Disord. 2008; 23: 474–83.
 
34.
Mizuma H, Takagi K, Miyake K, Takagi N, Ishida K, Takeo S, et al. Microsphere embolism-induced elevation of nerve growth factor level and appearance of nerve growth factor immunoreactivity in activated T-lymphocytes in the rat brain. J Neurosci Res. 1999; 55: 749–61.
 
35.
Barouch R, Appel E, Kazimirsky G, Braun A, Renz H, Brodie C. Differential regulation of neurotrophin expression by mitogens and neurotransmitters in mouse lymphocytes. J Neuroimmunol. 2000; 103: 112–21.
 
36.
Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A. The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse. Exp Neurol. 1999; 156: 50–61.
 
37.
Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW. ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow. Blood. 2005; 106: 584–92.
 
38.
Wu L, Walas S, Leung W, Sykes DB, Wu J, Lo EH, et al. Neuregulin1-beta Decreases IL-1beta-Induced Neutrophil Adhesion to Human Brain Microvascular Endothelial Cells. Transl Stroke Res. 2014.
 
39.
Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29: e45.
 
40.
Nagatsu T, Mogi M, Ichinose H, Togari A. Cytokines in Parkinson’s disease. J Neural Transm Suppl. 2000: 143–51.
 
41.
Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T (2005) Alterations of T-lymphocyte populations in Parkinson disease vol 11, 2005/09/13 edn. doi:10.1016/j.parkreldis.2005.07.005.
 
42.
Brodacki B, Staszewski J, Toczylowska B, Kozlowska E, Drela N, Chalimoniuk M, et al. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett. 2008; 441: 158–62.
 
43.
Rentzos M, Nikolaou C, Andreadou E, Paraskevas GP, Rombos A, Zoga M, et al. Circulating interleukin-10 and interleukin-12 in Parkinson’s disease. Acta Neurol Scand. 2009; 119: 332–7.
 
44.
Klegeris A, Giasson BI, Zhang H, Maguire J, Pelech S, McGeer PL. Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells. Faseb j. 2006; 20: 2000–8.
 
45.
Yuan Y, Sun J, Zhao M, Hu J, Wang X, Du G, et al. Overexpression of alpha-synuclein down-regulates BDNF expression. Cell Mol Neurobiol. 2010; 30: 939–46.
 
46.
Adamczyk A, Kazmierczak A, Czapski GA, Strosznajder JB. Alpha-synuclein induced cell death in mouse hippocampal (HT22) cells is mediated by nitric oxide-dependent activation of caspase-3. FEBS Lett. 2010; 584: 3504–8.
 
47.
Nishiguchi M, Tokugawa K, Yamamoto K, Akama T, Nozawa Y, Chaki S, et al. Increase in secretion of glial cell line-derived neurotrophic factor from glial cell lines by inhibitors of vacuolar ATPase. Neurochemistry International. 2003; 42: 493–498.
 
48.
Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol. 2003; 106: 518–26.
 
49.
Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR, et al. MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci. 2013; 33: 9592–600.
 
50.
Kustrimovic N, Rasini E, Legnaro M, Marino F, Cosentino M. Expression of dopaminergic receptors on human CD4+ T lymphocytes: flow cytometric analysis of naive and memory subsets and relevance for the neuroimmunology of neurodegenerative disease. J Neuroimmune Pharmacol. 2014; 9: 302–12.
 
51.
Zhang Q-S, Heng Y, Yuan Y-H, Chen N-H. Pathological α-synuclein exacerbates the progression of Parkinson’s disease through microglial activation. Toxicology Letters. 2017; 265: 30–37.
 
52.
Hoffmann A, Ettle B, Bruno A, Kulinich A, Hoffmann A-C, von Wittgenstein J, et al. Alpha-synuclein activates BV2 microglia dependent on its aggregation state. Biochemical and Biophysical Research Communications. 2016; 479: 881–886.
 
53.
Alvarez-Erviti L, Couch Y, Richardson J, Cooper JM, Wood MJA. Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neuroscience Research. 2011; 69: 337–342.
 
54.
Snead D,Eliezer D. Alpha-synuclein function and dysfunction on cellular membranes. Exp Neurobiol. 2014; 23: 292–313.
 
55.
Lee SJ, Drabik K, Van Wagoner NJ, Lee S, Choi C, Dong Y, et al. ICAM-1-induced expression of proinflammatory cytokines in astrocytes: involvement of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways. J Immunol. 2000; 165: 4658–66.
 
56.
Etienne-Manneville S, Chaverot N, Strosberg AD, Couraud PO. ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response element-binding protein phosphorylation and TNF-alpha secretion. J Immunol. 1999; 163: 668–74.
 
57.
Akiyama H, Kawamata T, Yamada T, Tooyama I, Ishii T, McGeer PL. Expression of intercellular adhesion molecule (ICAM)-1 by a subset of astrocytes in Alzheimer disease and some other degenerative neurological disorders. Acta Neuropathol. 1993; 85: 628–34.
 
58.
Tong J, Ang LC, Williams B, Furukawa Y, Fitzmaurice P, Guttman M, et al. Low levels of astroglial markers in Parkinson’s disease: relationship to alpha-synuclein accumulation. Neurobiol Dis. 2015; 82: 243–253.
 
59.
Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ. Platelet interleukin-1α drives cerebrovascular inflammation. Blood. 2010; 115: 3632–3639.
 
eISSN:1898-7516
ISSN:1898-2395