Mikroglial Toll-benzeri Reseptörlerin Alzheimer ve Parkinson Hastalıklarındaki Rolü

Öz

Patern tanıma reseptörleri içinde en iyi tanımlanmış olan Toll-benzeri reseptörler, santral sinir sisteminde ?makrofaj benzeri? fonksiyona sahip mikroglia hücrelerinde bulunurlar. Amiloid-beta proteini ve agrege ?-sinüklein gibi hasarla ilişkili moleküler motifleri tanıyan Toll-benzeri reseptörler, mikroglia hücrelerinin proinflamatuar fenotipe kaymasına neden olarak ve tümör nekroz faktör-alfa (TNF-?), interlökin (IL)-1, IL-6, IL-12 gibi proinflamatuar mediyatörler aracılığıyla inflamasyonu tetikler. Nörodejeneratif hastalıklarda mikroglial Toll-benzeri reseptör aracılı sinyalizasyonun önemli bir role sahip olduğu gösterildiği için Alzheimer ve Parkinson hastalıklarında (i) aşılar, (ii) küçük moleküllü inhibitörler, (iii) var olan ilaçların yeni bir endikasyon için kullanılması ve (iv) doğal bileşikler gibi Toll-benzeri reseptörleri hedef alan yeni tedavi yaklaşımları bulunmaktadır. Preklinik çalışmalarda başarılı sonuçlar göstermiş olan ilaç adaylarının birçoğu klinik fazlarda aynı başarıyı yakalayamamıştır. Buna rağmen, Toll-benzeri reseptörler ve sinyal yolakları üzerinde etkili moleküllerle ilgili çalışmaların sayısı artmaya devam etmektedir.

Anahtar Kelimeler

• Mikroglia
• Toll-benzeri reseptörler
• Alzheimer hastalığı
• Parkinson hastalığı

The Role of Microglial Toll-like Receptors in Alzheimer?s and Parkinson?s Disease

Abstract

Toll-like receptors, the best defined among the different pattern recognition receptors, are found on microglia cells that have a "macrophage-like" function in the central nervous system. Toll-like receptors that recognize damage-related molecular motifs such as amyloid-beta protein and aggregated ?-synuclein, trigger inflammation via switching the microglial phenotype to proinflammatory side and releasing proinflammatory mediators such as tumor necrosis factor-alpha (TNF-?), interleukin (IL)-1, IL-6, IL-12. Since Toll-like receptor-mediated signaling has been shown to play an important role in neurodegenerative diseases, there are new treatment approaches targeting Toll-like receptors including (i) vaccines, (ii) small molecule inhibitors, (iii) use of existing drugs for a new indication and (iv) use of natural compounds. Although many compounds have shown promising results in preclinical studies, they have not achieved the same success in clinical trials. However, the studies with compounds targeting Toll-like receptors and signaling cascades are continuing to increase.

Keywords

• Microglia
• Toll-like receptors
• Alzheimer?s disease
• Parkinson?s disease

References

1. 1. Wesselingh R, Butzkueven H, Buzzard K, Tarlinton D, O'Brien TJ, Monif M. Innate Immunity in the Central Nervous System: A Missing Piece of the Autoimmune Encephalitis Puzzle? Front Immunol 2019; 10:2066.
2. 2. Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med 2015; 3(10):136.
3. 3. Kumar V. Toll-like receptors in the pathogenesis of neuroinflammation. J Neuroimmunol 2019; 332:16-30.
4. 4. Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. Role of Microglia TLRs in Neurodegeneration. Front Cell Neurosci 2018; 12:329.
5. 5. Nie L, Cai SY, Shao JZ, Chen J. Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals. Front Immunol 2018; 9:1523.
6. 6. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4(7):499-511.
7. 7. Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol 2018; 37(1):20-36.
8. 8. Rangasamy SB, Jana M, Roy A, Corbett GT, Kundu M, Chandra S, Mondal S, Dasarathi S, Mufson EJ, Mishra RK, Luan CH, Bennett DA, Pahan K. Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology. J Clin Invest 2018; 128(10):4297-312.

9. 9. Udan ML, Ajit D, Crouse NR, Nichols MR. Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line. J Neurochem 2008; 104(2):524-33.
10. 10. McDonald CL, Hennessy E, Rubio-Araiz A, Keogh B, McCormack W, McGuirk P, Reilly M, Lynch MA. Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer's disease. Brain Behav Immun 2016; 58:191-200.
11. 11. Su F, Bai F, Zhou H, Zhang Z. Reprint of: Microglial toll-like receptors and Alzheimer's disease. Brain Behav Immun 2016; 55:166-78.
12. 12. Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, Rube CE, Walter J, Heneka MT, Hartmann T, Menger MD, Fassbender K. TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation. J Immunol 2012; 188(3):1098-107.
13. 13. Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, Lockett S, Dunlop NM, Wang JM. Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J Biol Chem 2006; 281(6):3651-9.
14. 14. Richard KL, Filali M, Prefontaine P, Rivest S. Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J Neurosci 2008; 28(22):5784-93.
15. 15. Heshmati-Fakhr N, Sotoodehnejadnematalahi F, Yousefi N, Sayyah M, Hosseini SM, Pourbadie HG. Triggering microglia through toll-like receptor 2 pathway induced interferon beta expression in cell and animal model of Alzheimer's disease. Neuroreport 2018; 29(17):1456-62.
16. 16. Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation 2008; 5:23.
17. 17. Balducci C, Frasca A, Zotti M, La Vitola P, Mhillaj E, Grigoli E, Iacobellis M, Grandi F, Messa M, Colombo L, Molteni M, Trabace L, Rossetti C, Salmona M, Forloni G. Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by beta-amyloid oligomers in an acute mouse model of Alzheimer's disease. Brain Behav Immun 2017; 60:188-97.
18. 18. Pourbadie HG, Sayyah M, Khoshkholgh-Sima B, Choopani S, Nategh M, Motamedi F, Shokrgozar MA. Early minor stimulation of microglial TLR2 and TLR4 receptors attenuates Alzheimer's disease-related cognitive deficit in rats: behavioral, molecular, and electrophysiological evidence. Neurobiol Aging 2018; 70:203-16.
19. 19. Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA, Kim HD, Tahara K, Lalonde R, Fukuchi K. TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease. J Neuroinflammation 2011; 8:92.
20. 20. Shintani Y, Drexler HC, Kioka H, Terracciano CM, Coppen SR, Imamura H, Akao M, Nakai J, Wheeler AP, Higo S, Nakayama H, Takashima S, Yashiro K, Suzuki K. Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2. EMBO Rep 2014; 15(4):438-45.
21. 21. Patel V, Patel AM, McArdle JJ. Synaptic abnormalities of mice lacking toll-like receptor (TLR)-9. Neuroscience 2016; 324:1-10.
22. 22. Scholtzova H, Chianchiano P, Pan J, Sun Y, Goni F, Mehta PD, Wisniewski T. Amyloid beta and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation. Acta Neuropathol Commun 2014; 2:101.
23. 23. Chakrabarty P, Li A, Ladd TB, Strickland MR, Koller EJ, Burgess JD, Funk CC, Cruz PE, Allen M, Yaroshenko M, Wang X, Younkin C, Reddy J, Lohrer B, Mehrke L, Moore BD, Liu X, Ceballos-Diaz C, Rosario AM, Medway C, Janus C, Li HD, Dickson DW, Giasson BI, Price ND, Younkin SG, Ertekin-Taner N, Golde TE. TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease. J Exp Med 2018; 215(9):2247-64.
24. 24. Gambuzza ME, Sofo V, Salmeri FM, Soraci L, Marino S, Bramanti P. Toll-like receptors in Alzheimer's disease: a therapeutic perspective. CNS Neurol Disord Drug Targets 2014; 13(9):1542-58.
25. 25. Grundman M, Kinney GG, Yuen E, Black R. Immunotherapy for Alzheimer’s Disease. In: Anil K. Nair, Sabbagh MN, eds. Geriatric Neurology. 1st ed. New Delhi, India: John Wiley & Sons, 2014:574-86.
26. 26. Muhs A, Hickman DT, Pihlgren M, Chuard N, Giriens V, Meerschman C, van der Auwera I, van Leuven F, Sugawara M, Weingertner MC, Bechinger B, Greferath R, Kolonko N, Nagel-Steger L, Riesner D, Brady RO, Pfeifer A, Nicolau C. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci U S A 2007; 104(23):9810-5.
27. 27. Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 2007; 316(5831):1628-32.
28. 28. Mirotti L, Alberca Custodio RW, Gomes E, Rammauro F, de Araujo EF, Garcia Calich VL, Russo M. CpG-ODN Shapes Alum Adjuvant Activity Signaling via MyD88 and IL-10. Front Immunol 2017; 8:47.
29. 29. Wang CY, Wang PN, Chiu MJ, Finstad CL, Lin F, Lynn S, Tai YH, De Fang X, Zhao K, Hung CH, Tseng Y, Peng WJ, Wang J, Yu CC, Kuo BS, Frohna PA. UB-311, a novel UBITh((R)) amyloid beta peptide vaccine for mild Alzheimer's disease. Alzheimers Dement (N Y) 2017; 3(2):262-72.
30. 30. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE. Parkinson disease. Nat Rev Dis Primers 2017; 3:17013.
31. 31. Lecours C, Bordeleau M, Cantin L, Parent M, Paolo TD, Tremblay ME. Microglial Implication in Parkinson's Disease: Loss of Beneficial Physiological Roles or Gain of Inflammatory Functions? Front Cell Neurosci 2018; 12:282.
32. 32. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS, Zhang J. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J 2005; 19(6):533-42.
33. 33. Kouli A, Horne CB, Williams-Gray CH. Toll-like receptors and their therapeutic potential in Parkinson's disease and alpha-synucleinopathies. Brain Behav Immun 2019; 81:41-51.
34. 34. Dzamko N, Gysbers A, Perera G, Bahar A, Shankar A, Gao J, Fu Y, Halliday GM. Toll-like receptor 2 is increased in neurons in Parkinson's disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol 2017; 133(2):303-19.
35. 35. Kim C, Ho DH, Suk JE, You S, Michael S, Kang J, Joong Lee S, Masliah E, Hwang D, Lee HJ, Lee SJ. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun 2013; 4:1562.
36. 36. La Vitola P, Balducci C, Cerovic M, Santamaria G, Brandi E, Grandi F, Caldinelli L, Colombo L, Morgese MG, Trabace L, Pollegioni L, Albani D, Forloni G. Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2. Brain Behav Immun 2018; 69:591-602.
37. 37. Koo JH, Jang YC, Hwang DJ, Um HS, Lee NH, Jung JH, Cho JY. Treadmill exercise produces neuroprotective effects in a murine model of Parkinson's disease by regulating the TLR2/MyD88/NF-kappaB signaling pathway. Neuroscience 2017; 356:102-13.
38. 38. Kim C, Spencer B, Rockenstein E, Yamakado H, Mante M, Adame A, Fields JA, Masliah D, Iba M, Lee HJ, Rissman RA, Lee SJ, Masliah E. Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating alpha-synuclein transmission and neuroinflammation. Mol Neurodegener 2018; 13(1):43.
39. 39. Mistry P, Laird MH, Schwarz RS, Greene S, Dyson T, Snyder GA, Xiao TS, Chauhan J, Fletcher S, Toshchakov VY, MacKerell AD, Jr., Vogel SN. Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain. Proc Natl Acad Sci U S A 2015; 112(17):5455-60.
40. 40. Rietdijk C, van Wezel R, Garssen J, Kraneveld A. Neuronal toll-like receptors and neuro-immunity in parkinson's disease, Alzheimer's disease and stroke. Neuroimmunology and neuroinflammation 2016; 3(2):27-37.
41. 41. Kalinderi K, Bostantjopoulou S, Katsarou Z, Fidani L. TLR9 -1237 T/C and TLR2 -194 to -174 del polymorphisms and the risk of Parkinson's disease in the Greek population: a pilot study. Neurol Sci 2013; 34(5):679-82.
42. 42. Drouin-Ouellet J, St-Amour I, Saint-Pierre M, Lamontagne-Proulx J, Kriz J, Barker RA, Cicchetti F. Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson's disease. Int J Neuropsychopharmacol 2014; 18(6).
43. 43. Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, Wenning GK, Stefanova N. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 2013; 61(3):349-60.
44. 44. Noelker C, Morel L, Lescot T, Osterloh A, Alvarez-Fischer D, Breloer M, Henze C, Depboylu C, Skrzydelski D, Michel PP, Dodel RC, Lu L, Hirsch EC, Hunot S, Hartmann A. Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci Rep 2013; 3:1393.
45. 45. Campolo M, Paterniti I, Siracusa R, Filippone A, Esposito E, Cuzzocrea S. TLR4 absence reduces neuroinflammation and inflammasome activation in Parkinson's diseases in vivo model. Brain Behav Immun 2019; 76:236-47.
46. 46. Stefanova N, Fellner L, Reindl M, Masliah E, Poewe W, Wenning GK. Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am J Pathol 2011; 179(2):954-63.
47. 47. Mariucci G, Pagiotti R, Galli F, Romani L, Conte C. The Potential Role of Toll-Like Receptor 4 in Mediating Dopaminergic Cell Loss and Alpha-Synuclein Expression in the Acute MPTP Mouse Model of Parkinson's Disease. J Mol Neurosci 2018; 64(4):611-18.
48. 48. Ros-Bernal F, Hunot S, Herrero MT, Parnadeau S, Corvol JC, Lu L, Alvarez-Fischer D, Carrillo-de Sauvage MA, Saurini F, Coussieu C, Kinugawa K, Prigent A, Hoglinger G, Hamon M, Tronche F, Hirsch EC, Vyas S. Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism. Proc Natl Acad Sci U S A 2011; 108(16):6632-7.
49. 49. Maatouk L, Compagnion AC, Sauvage MC, Bemelmans AP, Leclere-Turbant S, Cirotteau V, Tohme M, Beke A, Trichet M, Bazin V, Trawick BN, Ransohoff RM, Tronche F, Manoury B, Vyas S. TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons. Nat Commun 2018; 9(1):2450.
50. 50. Gao W, Xiong Y, Li Q, Yang H. Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics. Front Physiol 2017; 8:508.
51. 51. Hughes CD, Choi ML, Ryten M, Hopkins L, Drews A, Botia JA, Iljina M, Rodrigues M, Gagliano SA, Gandhi S, Bryant C, Klenerman D. Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis. Acta Neuropathol 2019; 137(1):103-20.
52. 52. Daniele SG, Beraud D, Davenport C, Cheng K, Yin H, Maguire-Zeiss KA. Activation of MyD88-dependent TLR1/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders. Sci Signal 2015; 8(376):ra45.
53. 53. Dasu MR, Riosvelasco AC, Jialal I. Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo. Atherosclerosis 2009; 202(1):76-83.
54. 54. Ping Z, Xiaomu W, Xufang X, Liang S. Vinpocetine regulates levels of circulating TLRs in Parkinson's disease patients. Neurol Sci 2019; 40(1):113-20.
55. 55. Yan J, Qiao L, Tian J, Liu A, Wu J, Huang J, Shen M, Lai X. Effect of statins on Parkinson's disease: A systematic review and meta-analysis. Medicine (Baltimore) 2019; 98(12):e14852.
56. 56. Yan JQ, Sun JC, Zhai MM, Cheng LN, Bai XL, Feng CL. Lovastatin induces neuroprotection by inhibiting inflammatory cytokines in 6-hydroxydopamine treated microglia cells. Int J Clin Exp Med 2015; 8(6):9030-7.
57. 57. Peng Y, Zhang X, Zhang T, Grace PM, Li H, Wang Y, Li H, Chen H, Watkins LR, Hutchinson MR, Yin H, Wang X. Lovastatin inhibits Toll-like receptor 4 signaling in microglia by targeting its co-receptor myeloid differentiation protein 2 and attenuates neuropathic pain. Brain Behav Immun 2019; 82:432-44.
58. 58. Molteni M, Bosi A, Rossetti C. Natural Products with Toll-Like Receptor 4 Antagonist Activity. Int J Inflam 2018; 2018:2859135.
59. 59. Yu Z, Wan Y, Liu Y, Yang J, Li L, Zhang W. Curcumin induced apoptosis via PI3K/Akt-signalling pathways in SKOV3 cells. Pharm Biol 2016; 54(10):2026-32.
60. 60. Zeng KW, Zhang T, Fu H, Liu GX, Wang XM. Schisandrin B exerts anti-neuroinflammatory activity by inhibiting the Toll-like receptor 4-dependent MyD88/IKK/NF-kappaB signaling pathway in lipopolysaccharide-induced microglia. Eur J Pharmacol 2012; 692(1-3):29-37.