The role of infectious agents in the development of neurodegenerative diseases

Abstract

Actually, there is no consensus about the causes of the development in most neurodegenerative diseases. Recent international publications describe various hypotheses of the genesis of such diseases. Infectious is considered as one of them, assuming an infectious agent can trigger a cascade of pathological processes that eventually lead to the manifestation of various neurodegenerative diseases. The direct relationship between infectious invasion and the development of neurodegenerative diseases is not fully proved yet, but these publications confirm the hypothesis that a variety of pathogens (viruses, bacteria, intracellular parasites etc.) can induce the process of neuronal inflammation with subsequent neurodegeneration. As a result of the scientific research, various ways of penetration of infectious agents into the central nervous system have been studied and proven. In the case of neuroinfections already studied, inflammatory and alterative changes in nervous tissue occur with the direct participation of neuroglia and cells of the immune system, which may be part of the universal trigger mechanism of the neurodegenerative process. At the same time, in the case of a number of diseases, the primary role of specific infectious agents is possible. It has been shown that neurological complications of a novel coronavirus infection can also occur as a result of both direct cytopathic action of the pathogen or activation of neuroinflammation processes. Of course, this hypothesis of neurodegenerative pathology requires a comprehensive analysis and subsequent confirmation, however, the investigation of molecular and cellular mechanisms of neuroinflammation and neurodegeneration already opens up broad prospects for finding possible pathogenetic therapy of these diseases (bibliography: 42 refs)

Keywords

infectious agents / mechanisms of invasion / microglia / neurodegenerative diseases / neuroinflammation / neurotropic pathogens / proteinopathy

References

[1] Berth SH. Virus-induced neuronal dysfunction and degeneration. Front Biosci. 2009;14(1):5239–5259. DOI: 10.2741/3595

[2] Berth S.H. Virus-induced neuronal dysfunction and degeneration // Front. Biosci. 2009. Vol. 14, No. 1. P. 5239–5259. DOI: 10.2741/3595

[3] Wouk J, Rechenchoski DZ, Rodrigues BCD, et al. Viral infections and their relationship to neurological disorders. Arch Virol. 2021;166:733–753. DOI: 10.1007/s00705-021-04959-6

[4] Wouk J., Rechenchoski D.Z., Rodrigues B.C.D., et al. Viral infections and their relationship to neurological disorders // Arch. Virol. 2021. No. 166. P. 733–753. DOI: 10.1007/s00705-021-04959-6

[5] Alzheimer A, Stelzmann RA, Schnitzlein HN, et al. An English translation of Alzheimer’s 1907 paper, “Über eine eigenartige Erkrankung der Hirnrinde”. Clin Anat. 1995;8:429–431. DOI: 10.1002/ca.980080612

[6] Alzheimer A., Stelzmann R.A., Schnitzlein H.N., et al. An English translation of Alzheimer’s 1907 paper, «Über eine eigenartige Erkrankung der Hirnrinde» // Clin. Anat. 1995. No. 8. P. 429–431. DOI: 10.1002/ca.980080612

[7] Liddelow S, Guttenplan K, Clarke L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541: 481–487. DOI: 10.1038/ nature21029

[8] Liddelow S., Guttenplan K., Clarke L., et al. Neurotoxic reactive astrocytes are induced by activated microglia // Nature. 2017. No. 541. P. 481–487. DOI: 10.1038/nature21029

[9] Richards A, Berth SH, Brady S, et al. Engagement of Neurotropic Viruses in Fast Axonal Transport: Mechanisms, Potential Role of Host Kinases and Implications for Neuronal Dysfunction. Front Cell Neurosci. 2021;15: 684762. DOI: 10.3389/fncel. 2021.684762

[10] Richards A., Berth S.H., Brady S., et al. Engagement of Neurotropic Viruses in Fast Axonal Transport: Mechanisms, Potential Role of Host Kinases and Implications for Neuronal Dysfunction // Front. Cell Neurosci. 2021. No. 15. P. 684762. DOI: 10.3389/fncel.2021.684762

[11] Pan-Montojo F, Schwarz M, Winkler C, et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep. 2012;2(1):898. DOI: 10.1038/srep00898

[12] Pan-Montojo F., Schwarz M., Winkler C., et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice // Sci. Rep. 2012. Vol. 2, No. 1. P. 898. DOI: 10.1038/srep00898

[13] Svensson E, Horváth-Puhó E, Thomsen RW, et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol. 2015;78: 522–529. DOI: 10.1002/ ana.24448

[14] Svensson E., Horváth-Puhó E., Thomsen R.W., et al. Vagotomy and subsequent risk of Parkinson’s disease // Ann. Neurol. 2015. No. 78. P. 522–529. DOI: 10.1002/ana.24448

[15] Gosztyla ML, Brothers HM, Robinson SR. Alzheimer’s amyloid-β is an antimicrobial peptide: a review of the evidence. J Alzheimers Dis. 2018;62:1495–1506. DOI: 10.3233/jad-171133

[16] Gosztyla M.L., Brothers H.M., Robinson S.R. Alzheimer’s amyloid-β is an antimicrobial peptide: a review of the evidence // J. Alzheimers Dis. 2018. No. 62. P. 1495–1506. DOI: 10.3233/jad-171133

[17] Bourgade K, Garneau H, Giroux G, et al. β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology. 2014;16(1):85–98. DOI: 10.1007/s10522-014-9538-8

[18] Bourgade K., Garneau H., Giroux G., et al. β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1 // Biogerontology. 2014. Vol. 16, No. 1. P. 85–98. DOI: 10.1007/s10522-014-9538-8

[19] Bourgade K, Le Page A, Bocti C, et al. Protective effect of amyloid-β peptides against herpes simplex virus-1 infection in a neuronal cell culture model. J Alzheimers Dis. 2016;50(4):1227–1241. DOI: 10.3233/jad-150652

[20] Bourgade K., Le Page A., Bocti C., et al. Protective effect of amyloid-β peptides against herpes simplex virus-1 infection in a neuronal cell culture model // J. Alzheimers Dis. 2016. Vol. 50, No. 4. P. 1227–1241. DOI: 10.3233/jad-150652

[21] Kumar DKV, Choi SH, Washicosky KJ, et al. Amyloid-β peptide protects against microbial infection in mouse and worm mo dels of Alzheimer’s disease. Sci Transl Med. 2016;8(340):340ra72. DOI: 10.1126/scitranslmed.aaf1059

[22] Kumar D.K.V., Choi S.H., Washicosky K.J., et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease // Sci. Transl. Med. 2016. Vol. 8, No. 340. P. 340ra72. DOI: 10.1126/scitranslmed.aaf1059

[23] Vigasova D, Nemergut M, Liskova B, et al. Multi-pathogen infections and Alzheimer’s disease. Microb Cell Fact. 2021;20(1):25. DOI: 10.1186/s12934-021-01520-7

[24] Vigasova D., Nemergut M., Liskova B., et al. Multi-pathogen infections and Alzheimer’s disease // Microb. Cell Fact. 2021. Vol. 20, No. 1. P. 25. DOI: 10.1186/s12934-021-01520-7

[25] Miklossy J, Kis A, Radenovic A, et al. Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging. 2006;27:228–236. DOI: 10.1016/j.neurobiolaging.2005.01.018

[26] Miklossy J., Kis A., Radenovic A., et al. Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes // Neurobiol. Aging. 2006. No. 27. P. 228–236. DOI: 10.1016/j.neurobiolaging.2005.01.018

[27] Nayeri T, Sarvi S, Sharif M, et al. Toxoplasma gondii: A possible etiologic agent for Alzheimer’s disease. Heliyon. 2021;7(6):e07151. DOI: 10.1016/j.heliyon. 2021.e07151

[28] Nayeri T., Sarvi S., Sharif M., et al. Toxoplasma gondii: A possible etiologic agent for Alzheimer’s disease // Heliyon. 2021. Vol. 7, No. 6. P. e07151. DOI: 10.1016/j.heliyon. 2021.e07151

[29] Poole S, Singhrao SK, Chukkapalli S, et al. Active Invasion of Porphyromonas gingivalis and Infection-Induced Complement Activation in ApoE-/-mice Brains. J Alzheimers Dis. 2015;43:67–80. DOI: 10.3233/jad-140315

[30] Poole S., Singhrao S.K., Chukkapalli S., et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/-mice brains // J. Alzheimers Dis. 2015. No. 43. P. 67–80. DOI: 10.3233/jad-140315

[31] Wang T, Town T, Alexopoulou L, et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med. 2004;10(12):1366–1373. DOI: 10.1038/nm1140

[32] Wang T., Town T., Alexopoulou L., et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis // Nat. Med. 2004. Vol. 10, No. 12. P. 1366–1373. DOI: 10.1038/nm1140

[33] Bsibsi M, Ravid R, Gveric D, et al. Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002;61(11):1013–1021. DOI: 10.1093/jnen/61.11.1013

[34] Bsibsi M., Ravid R., Gveric D., et al. Broad expression of Toll-like receptors in the human central nervous system // J. Neuropathol. Exp. Neurol. 2002. Vol. 61, No. 11. P. 1013–1021. DOI: 10.1093/jnen/61.11.1013

[35] Lewandowski G, Zimmerman MN, Denk LL, et al. Herpes simplex type 1 infects and establishes latency in the brain and trigeminal ganglia during primary infection of the lip in cotton rats and mice. Arch Virol. 2002;147:167–179. DOI: 10.1007/s705-002-8309-9

[36] Lewandowski G., Zimmerman M.N., Denk L.L., et al. Herpes simplex type 1 infects and establishes latency in the brain and trigeminal ganglia during primary infection of the lip in cotton rats and mice // Arch. Virol. 2002. No. 147. P. 167–179. DOI: 10.1007/ s705-002-8309-9

[37] Mori I, Goshima F, Ito H, et al. The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus. Virology. 2005;334:51–58. DOI: 10.1016/j.virol.2005.01.023

[38] Mori I., Goshima F., Ito H., et al. The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus // Virology. 2005. No. 334. P. 51–58. DOI: 10.1016/j.virol.2005.01.023

[39] Eimer WA, Kumar DK, Shanmugam NK, et al. Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron. 2018;99(1):56–63. DOI: 10.1016/j.neuron.2018.06.030

[40] Eimer W.A., Kumar D.K., Shanmugam N.K., et al. Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection // Neuron. 2018. Vol. 99, No. 1. P. 56–63. DOI: 10.1016/j.neuron.2018.06.030

[41] Wozniak MA, Itzhaki RF, Shipley SJ, et al. Herpes simplex virus infection causes cellular-amyloid accumulation and secretase upregulation. Neurosci Lett. 2007;429:95–100. DOI: 10.1016/j.neulet.2007.09.077

[42] Wozniak M.A., Itzhaki R.F., Shipley S.J., et al. Herpes simplex virus infection causes cellular-amyloid accumulation and secretase upregulation // Neurosci. Lett. 2007. No. 429. P. 95–100. DOI: 10.1016/j.neulet.2007.09.077

[43] Zambrano A, Solis L, Salvadores N, et al. Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1. J Alzheimers Dis. 2008;14:259–269. DOI: 10.3233/jad-2008-14301

[44] Zambrano A., Solis L., Salvadores N., et al. Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1 // J. Alzheimers Dis. 2008. No. 14. P. 259–269. DOI: 10.3233/jad-2008-14301

[45] Piacentini R, Civitelli L, Ripoli C, et al. HSV-1 promotes Ca2+-mediated APP phosphorylation and Aβ accumulation in rat cortical neurons. Neurobiol Aging. 2011;32:2323.e13–2323.e26. DOI: 10.1016/j.neurobiolaging.2010.06.009

[46] Piacentini R., Civitelli L., Ripoli C., et al. HSV-1 promotes Ca2+-mediated APP phosphorylation and Aβ accumulation in rat cortical neurons // Neurobiol. Aging. 2011. No. 32. P. 2323.e13–2323.e26. DOI: 10.1016/j.neurobiolaging.2010.06.009

[47] Jang H, Boltz D, Sturm-Ramirez K, et al. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci. 2009;106:14063–14068. DOI: 10.1073/ pnas.0900096106

[48] Jang H., Boltz D., Sturm-Ramirez K., et al. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration // Proc. Natl. Acad. Sci. 2009. No. 106. P. 14063–14068. DOI: 10.1073/ pnas.0900096106

[49] Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33(6):599–614. DOI: 10.1111/j.1365-2990.2007.00874.x

[50] Hawkes C.H., Del Tredici K., Braak H. Parkinson’s disease: a dual-hit hypothesis // Neuropathol. Appl. Neurobiol. 2007. Vol. 33, No. 6. P. 599–614. DOI: 10.1111/j.1365-2990.2007.00874.x

[51] Krasakov IV, Litvinenko IV, Rodionov GG, et al. Evaluation of gut microbiota in parkinson’s disease using gas chromatography with mass spectrometric detection. Ann Clin Exp Neur. 2018;12(4): 23–29. (In Russ.) DOI: 10.1134/s036211971908005x

[52] Красаков И.В., Литвиненко И.В., Родионов Г.Г., и др. Оценка микробиоты кишечника у пациентов с болезнью Паркинсона с помощью метода газовой хромато-масс-спектрометрии // Анналы клинической и экспериментальной неврологии. 2018. Т. 12, № 4. С. 23–29. DOI: 10.1134/s036211971908005x

[53] Labrie V, Brundin P. Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection. J Innate Immun. 2017;9(5):437–440. DOI: 10.1159/000479653

[54] Labrie V., Brundin P. Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection // J. Innate. Immun. 2017. Vol. 9, No. 5. P. 437–440. DOI: 10.1159/000479653

[55] Lotz SK, Blackhurst BM, Reagin, KL, et al. Microbial Infections Are a Risk Factor for Neurodegenerative Diseases. Front Cell Neurosci. 2021;15: 691136. DOI: 10.3389/fncel.2021.691136

[56] Lotz S.K., Blackhurst B.M., Reagin, K.L., et al. Microbial Infections Are a Risk Factor for Neurodegenerative Diseases // Front. Cell Neurosci. 2021. No. 15. P. 691136. DOI: 10.3389/fncel.2021.691136

[57] Alenina N, Bader M. ACE2 in brain physiology and pathophysio logy: evidence from transgenic animal models. Neurochem Res. 2019; 44(6):1323–1329. DOI: 10.1007/ s11064-018-2679-4

[58] Alenina N., Bader M. ACE2 in brain physiology and pathophysiology: evidence from transgenic animal models // Neurochem. Res. 2019. Vol. 44, No. 6. P. 1323–1329. DOI: 10.1007/s11064-018-2679-4

[59] Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020; 581(7807):215–220. DOI: 10.1038/s41586-020-2180-5

[60] Lan J., Ge J., Yu J., et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor // Nature. 2020. Vol. 581, No. 7807. P. 215–220. DOI: 10.1038/s41586-020-2180-5

[61] Heurich A, Hofmann-Winkler H, Gierer S, et al. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014;88(2): 1293–1307. DOI: 10.1128/jvi.02202-13

[62] Heurich A., Hofmann-Winkler H., Gierer S., et al. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein // J. Virol. 2014. Vol. 88, No. 2. P. 1293–1307. DOI: 10.1128/jvi.02202-13

[63] Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–280. DOI: 10.1016/j.cell.2020.02.052

[64] Hoffmann M., Kleine-Weber H., Schroeder S., et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor // Cell. 2020. Vol. 181, No. 2. P. 271–280. DOI: 10.1016/j.cell.2020.02.052.

[65] Chen Z, Mi L, Xu J, et al. Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus. J Infect Dis. 2005;191(5):755–760. DOI: 10.1086/427811

[66] Chen Z., Mi L., Xu J., et al. Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus // J. Infect. Dis. 2005. Vol. 191, No. 5. P. 755–760. DOI: 10.1086/427811

[67] Baig AM, Khaleeq A, Ali U, et al. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020;11(7): 995–998. DOI: 10.1021/ acschemneuro.0c00122

[68] Baig A.M., Khaleeq A., Ali U., et al. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms // ACS Chem. Neurosci. 2020. Vol 11, No. 7. P. 995–998. DOI: 10.1021/ acschemneuro.0c00122

[69] Bender SJ, Phillips JM, Scott EP, et al. Murine Coronavirus Receptors Are Differentially Expressed in the Central Nervous System and Play Virus Strain-Dependent Roles in Neuronal Spread. J Virol. 2010;84(21):11030–11044. DOI: https://doi.org/10.1128/jvi.02688-09

[70] Bender S.J., Phillips J.M., Scott E.P., et al. Murine Coronavirus Receptors Are Differentially Expressed in the Central Nervous System and Play Virus Strain-Dependent Roles in Neuronal Spread // J. Virol. 2010. Vol. 84, No. 21. P. 11030–11044. DOI: 10.1128/jvi.02688-09

[71] Finsterer J, Stollberger C. Update on the neurology of COVID-19. J Med Virol. 2020;92(11):2316–2318. DOI: 10.1002/jmv.26000

[72] Finsterer J., Stollberger C. Update on the neurology of COVID-19 // J. Med. Virol. 2020. Vol. 92, No. 11. P. 2316–2318. DOI: 10.1002/jmv.26000

[73] Kumar A, Pareek V, Prasoon P, et al. Possible routes of SARS-CoV-2 invasion in brain: In context of neurological symptoms in COVID-19 patients. J Neurosci Res. 2020;98(12):2376–2383. DOI: 10.1002/jnr.24717

[74] Kumar A., Pareek V., Prasoon P., et al. Possible routes of SARS-CoV-2 invasion in brain: In context of neurological symptoms in COVID-19 patients // J. Neurosci. Res. 2020. Vol. 98, No. 12. P. 2376–2383. DOI: 10.1002/jnr.24717

[75] Najjar S, Najjar A, Chong DJ, et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflamm. 2020;(17):231. DOI: 10.1186/s12974-020-01896-0

[76] Najjar S., Najjar A., Chong D.J., et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports // J. Neuroinflamm. 2020. No. 17. P. 231. DOI: 10.1186/s12974-020-01896-0

[77] Zubair AS, McAlpine LS, Gardin T, et al. Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019. JAMA Neurol. 2020;77(8):1018. DOI: 10.1001/jamaneurol.2020.2065

[78] Zubair A.S., McAlpine L.S., Gardin T., et al. Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019 // JAMA Neurol. 2020. Vol. 77, No. 8. P. 1018. DOI: 10.1001/jamaneurol.2020.2065

[79] Plog BA, Nedergaard M. The Glymphatic System in Central Nervous System Health and Disease: Past, Pre sent, and Future. Ann Rev Pathol. 2018;13(1): 379–394. DOI: 10.1146/annurev-pathol-051217-111018

[80] Plog B.A., Nedergaard M. The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future // Annu. Rev. Pathol. 2018. Vol. 13, No. 1. P. 379–394. DOI: 10.1146/annurev-pathol-051217-111018

[81] Netland J, Meyerholz DK, Moore S, et al. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 2008; 82(15):7264–7275. DOI: 10.1128/ jvi.00737-08

[82] Netland J., Meyerholz D.K., Moore S., et al. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2 // J. Virol. 2008. Vol. 82, No. 15. P. 7264–7275. DOI: 10.1128/ jvi.00737-08

[83] Zaitsev AA, Savushkina OI, Chernyak AV, et al. Clinical and functional characteristics of patients who recovered from the novel coronavirus infection (COVID-19). Prakticheskaya pul’monologiya. 2020;1:78–81. (In Russ.)

[84] Зайцев А.А., Савушкина О.И., Черняк А.В., и др. Клинико-функциональная характеристика пациентов, перенесших новую коронавирусную инфекцию COVID-19 // Практическая пульмонология. 2020. № 1. С. 78–81.

RIGHTS & PERMISSIONS

Litvinenko I.V., Lobzin V.Y., Pushkarev V.A.