Infectious hypothesis of neurodegenerative diseases. What waits us after the COVID-19 pandemic?
https://doi.org/10.30629/2658-7947-2022-27-3-64-73
Abstract
Since the description of the first clinical cases of the most common neurodegenerative diseases, numerous hypotheses have been proposed for their development. At the same time, the failure of therapeutic strategies in various directions of clinical research indicates the fallacy of most theories. In this regard, in recent years, various infectious agents are increasingly considered as a trigger of neuronal inflammation and a factor inducing the onset of the neurodegenerative process. Infectious agents differ in their mechanisms of invasion into the central nervous system and can even enter the brain perineurally. Reactivation of latent viral infection induces the production of viral proteins and the accumulation of abnormal proteins that are markers of Alzheimer’s disease and Parkinson’s disease. Both bacterial (chlamydia, causative agents of chronic periodontitis, E. coli) and viral (herpes viruses, noroviruses) infectious agents are considered. However, for the development of neurodegeneration, it is not enough just a simple invasion and reactivation of the infectious process: the genetic characteristics of the main histocompatibility complex also play a huge role. Currently, several studies have been initiated on the possible efficacy of antibacterial and antiviral drugs in Alzheimer’s disease. Data obtained over the past year suggests that the brain may act as a target for SARS-CoV-2. Neurological manifestations of COVID-19 can occur as a result of both the direct cytopathic action of the pathogen and the activation of neuroinflammation, accompanied by a violation of the integrity of the blood-brain barrier. Further study of the molecular and cellular mechanisms of neuroinflammation and neurodegeneration in COVID-19 will form the basis for the development of treatments for neurological complications.
About the Authors
I. V. Litvinenko
Military Medical Academy named after S.M. Kirov
Russian Federation
Russian Federation
St. Petersburg
V. Yu. Lobzin
Military Medical Academy named after S.M. Kirov; Children’s Research and Clinical Center for Infectious Diseases
Russian Federation
Russian Federation
St. Petersburg
V. A. Pushkarev
Military Medical Academy named after S.M. Kirov
Russian Federation
Russian Federation
St. Petersburg
N. V. Skripchenko
Children’s Research and Clinical Center for Infectious Diseases
Russian Federation
Russian Federation
St. Petersburg
References
1. Литвиненко И.В., Емелин А.Ю., Лобзин В.Ю., Колмакова К.А., Наумов К.М., Лупанов И.А. и др. Амилоидная гипотеза болезни Альцгеймера: прошлое и настоящее, надежды и разочарования. Неврология, нейропсихиатрия, психосоматика. 2019;11(3):4–10. [Litvinenko I.V., Emelin A.Yu., Lobzin V.Yu., Kolmakova K.A., Naumov K.M., Lupanov I.A. et al. The amyloid hypothesis of Alzheimer’s disease: past and present, hopes and disappointments. Neurology, Neuropsychiatry, Psychosomatics. 2019;11(3):4–10. (In Russ.)]. https://doi.org/10.14412/2074-2711-2019-3-4-10
2. Lewandowski G., Zimmerman M.N., Denk L.L., Porter D.D., Prince G.A. 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;147:167–79. https://doi.org/10.1007/s705-002-8309-9
3. Mori I., Goshima F., Ito H., Koide N., Yoshida T., Yokochi T. et al. The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus. Virology. 2005;334:51–8.
4. Prokop S., Lee V.M.Y., Trojanowski J.Q. Neuroimmune interactions in Alzheimer’s disease-New frontier with old challenges? Prog Mol Biol Transl Sci. 2019;168:183–201. https://doi:10.1016/bs.pmbts.2019.10.002
5. Лобзин В.Ю., Литвиненко И.В., Скрипченко Н.В., Скрипченко Е.Ю., Струментова Е.С. Роль возбудителей бактериальных и вирусных инфекций в инициации нейродегенеративных заболеваний. Журнал инфектологии. 2021;13(1–1):77–78. [Lobzin V.Yu., Litvinenko I.V., Skripchenko N.V., Skripchenko E.Yu., Strumentova E.S. The role of causative agents of bacterial and viral infections in the initiation of neurodegenerative diseases. Journal Infectology. 2021;13(1– 1):77–78. (In Russ.)].
6. Фисун А.Я., Черкашин Д.В., Макиев Р.Г., Кириченко П.Ю. «Очаговая инфекция» — фактор риска или патогенетическая основа возникновения заболеваний системы кровообращения. Вестник Российской военно-медицинской академии. 2015;3(51):7–16. [Fisun A.Ya., Cherkashin D.V., Makiev R.G., Kirichenko P.Yu. “Focal infection” — risk factor or pathogenetic basis of developing cardiovascular diseases. Bulletin of the Russian Military medical academy. 2015;3(51):7–16. (In Russ.)].
7. Bourgade K., Garneau H., Giroux G., Le Page A.Y., Bocti C., Dupuis G. et al. β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology. 2015;16:85–98. https://doi.org/10.1007/s10522-014-9538-8
8. Bourgade K., Le Page A.Y., Bocti C., Witkowski J.M., Dupuis G., Frost E.H., Fülöp T.Jr. Protective effect of amyloid-β peptides against herpes simplex virus-1 infection in a neuronal cell culture model. J. Alzheimers Dis. 2016;50(4):1227–41. https://doi.org/0.3233/JAD-150652
9. Kumar D.K., Choi S.H., Washicosky K.J., Eimer W.A., Tucker S., Ghofrani J. et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci. transl. med. 2016;8(340):340ra72. https://doi.org/10.1126/scitranslmed.aaf1059
10. Luna S., Cameron D.J., Ethell D.W. Amyloid-β and APP deficiencies cause severe cerebrovascular defects: important work for an old villain. PLoS One. 2013;8(9):e75052. https://doi.org/10.1371/journal.pone.0075052
11. 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;62(4):1495–506. https://doi.org/10.3233/JAD-171133
12. Atwood C.S., Bowen R.L., Smith M.A., Perry G. Cerebrovascular requirement for sealant, anti-coagulant and remodeling molecules that allow for the maintenance of vascular integrity and blood supply. Brain Res. Rev. 2003;43(1):164–78. https://doi.org/10.1016/s0165-0173(03)00206-6
13. Pajoohesh-Ganji A., Burns M.P., Pal-Ghosh S., Tadvalkar G., Hokenbury N.G., Stepp M.A. et al. Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury. Brain Res. 2014;1560:73–82. https://doi.org/10.1016/j.brainres.2014.02.049
14. Morley J.E., Farr S.A. The role of amyloid-beta in the regulation of memory. Biochem. Pharmacol. 2014;88(4):479–85. https://doi.org/10.1016/j.bcp.2013.12.018
15. Alzheimer A., Stelzmann R.A., Schnitzlein H.N., Murtagh F.R. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin. Anat. 1995;8(6):429– 31. https://doi.org/10.1002/ca.980080612
16. Little C.S., Hammond C.J., MacIntyre A., Balin B.J., Appelt D.M. Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiol. Aging. 2004;25(4):419– 29. https://doi.org/10.1016/S0197-4580(03)00127-1
17. Poole S., Singhrao S.K., Chukkapalli S., Rivera M., Velsko I., Kesavalu L. et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. J. Alzheimers Dis. 2015;43(1):67–80. https://doi.org/10.3233/JAD-140315
18. Ide M., Harris M., Stevens A., Sussams R., Hopkins V., Culliford D. et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One. 2016;11(3):e0151081. https://doi.org/10.1371/journal.pone.0151081
19. Mougeot J.-L.C., Stevens C.B., Paster B.J., Brennan M.T., Lockhart P.B., Mougeot F.K.B. Porphyromonas gingivalis is the most abundant species detected in coronary and femoral arteries. J. Oral Microbiol. 2017;9(1):1281562. https://doi.org/10.1080/20002297.2017.1281562
20. Dominy S.S., Lynch C., Ermini F. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv. 2019;5(1):eaau3333. https://doi.org/10.1126/sciadv.aau3333
21. Wang T., Town T., Alexopoulou L., Anderson J.F., Fikrig E., Flavell R.A. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 2004;10(12):1366–73. https://doi.org/10.1038/nm1140
22. Bsibsi M., Ravid R., Gveric D., van Noort J.M. Broad expression of Toll-like receptors in the human central nervous system. J. Neuropathol. Exp. Neurol. 2002;61(11):1013–21. https://doi.org/10.1093/jnen/61.11.1013
23. Itzhaki R.F., Golde T.E., Heneka M.T., Readhead B. Do infections have a role in the pathogenesis of Alzheimer disease? Nat. Rev. Neurol. 2020;16(4):193–7. https://doi.org/10.1038/s41582-020-0323-9
24. Wozniak M.A., Itzhaki R.F., Shipley S.J., Dobson C.B. Herpes simplex virus infection causes cellular-amyloid accumulation and secretase upregulation. Neurosci. Lett. 2007;429(2–3):95– 100. https://doi.org/10.1016/j.neulet.2007.09.077
25. Zambrano A., Solis L., Salvadores N., Cortés M., Lerchundi R., Otth C. Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1. J. Alzheimers Dis. 2008;14(3):259–69. https://doi.org/10.3233/jad-2008-14301
26. Piacentini R., Civitelli L., Ripoli C., Marcocci M.E., De Chiara G., Garaci E. et al. HSV-1 promotes Ca2+-mediated APP phosphorylation and Aβ accumulation in rat cortical neurons. Neurobiol. Aging. 2011;32(12):2323.e13–26. https://doi.org/10.1016/j.neurobiolaging.2010.06.009
27. Jang H., Boltz D., Sturm-Ramirez K., Shepherd K.R., Jiao Y., Webster R., Smeyne R.J. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc. Natl. Acad. Sci. USA. 2009;106(33):14063–8. https://doi.org/10.1073/pnas.0900096106
28. Hawkes C.H., Del Tredici K., Braak H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 2007;33(6):599– 614. https://doi.org/10.1111/j.1365-2990.2007.00874.x
29. Красаков И.В., Литвиненко И.В., Родионов Г.Г., Шантырь И.И., Светкина Е.В. Оценка микробиоты кишечника у пациентов с болезнью Паркинсона с помощью метода газовой хромато-масс-спектрометрии. Анналы клинической и экспериментальной неврологии. 2018;12(4):23–29. [Krasakov I.V., Litvinenko I.V., Rodionov G.G., Shantyr I.I., Svetkina E.V. Evaluation of gut microbiota in Parkinson’s disease using gas chromatography with mass spectrometric detection. Annals of clinical and experimental neurology. 2018;12(4):23– 29. (In Russ.)]. https://doi.org/10.25692/ACEN.2018.4.3
30. Labrie V., Brundin P. Alpha-synuclein to the rescue: immune cell recruitment by alpha-synuclein during gastrointestinal infection. J. Innate Immun. 2017;9(5):437–40. https://doi.org/10.1159/000479653
31. Литвиненко И.В., Красаков И.В., Бисага Г.Н., Скулябин Д.И., Полтавский И.Д. Cовременная концепция патогенеза нейродегенеративных заболеваний и стратегия терапии.Журналневрологии и психиатрии им. C.C. Корсакова. 2017;117(6–2):3– 10. [Litvinenko I.V., Krasakov I.V., Bisaga G.N., Skulyabin D.I., Poltavsky I.D. Modern conception of the pathogenesis of neurodegenerative diseases and therapeutic strategy. Korsakov Journal of neurology and psychiatry. 2017;117(6–2):3–10. (In Russ.)]. https://doi.org/10.17116/jnevro2017117623-10
32. Pan-Montojo F., Schwarz M., Winkler C., Arnhold M., O’Sullivan G.A., Pal A. et al. Environmental toxins trigger PDlike progression via increased alpha-synuclein release from enteric neurons in mice. Sci. Rep. 2012;2:898. https://doi.org/10.1038/srep00898
33. Svensson E., Horváth-Puhó E., Thomsen R.W., Djurhuus J.C., Pedersen L., Borghammer P. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 2015;78(4):522–9. https://doi.org/10.1002/ana.24448
34. Eimer W.A., Vijaya Kumar D.K., Navalpur Shanmugam N.K., Rodriguez A.S., Mitchell T., Washicosky K.J. et al. Alzheimer’s disease-associated β-amyloid is rapidly seeded by Herpesviridae to protect against brain infection. Neuron. 2018;99(1):56–63. https://doi.org/10.1016/j.neuron.2018.06.030
35. Waubant E., Mowry E.M., Krupp L., Chitnis T., Yeh E.A., Kuntz N. et al. US Pediatric MS Network. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology. 2011;76(23):1989–95. https://doi.org/10.1212/WNL.0b013e31821e552a
36. Alvarez-Lafuente R., De las Heras V., Bartolomé M., Picazo J.J., Arroyo R. Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection. Arch. Neurol. 2004;61(10):1523–7. https://doi.org/10.1001/archneur.61.10.1523
37. Salvetti M., Giovannoni G., Aloisi F. Epstein–Barr virus and multiple sclerosis. Curr. Opin. Neurol. 2009;22(3):201–6. https://doi.org/10.1097/WCO.0b013e32832b4c8d
38. Скрипченко Е.Ю., Железникова Г.Ф., Алексеева Л.А., Скрипченко Н.В., Астапова А.В. и др. Герпес-вирусы и биомаркеры при диссеминированном энцефаломиелите и рассеянном склерозе у детей. Журнал неврологии и психиатрии им. С.С. Корсакова. 2021;121(3):138–145. [Skripchenko E.Yu, Zheleznikova G.F., Alekseeva L.A., Skripchenko N.V., Astapova A.V. Herpesviruses and biomarkers in disseminated encephalomyelitis and multiple sclerosis in children. Korsakov Journal of neurology and psychiatry. 2021;121(3):138–145. (In Russ.)]. https://doi.org/10.17116/jnevro2021121031138
39. Алисейчик М.П., Андреева Т.В., Рогаев Е.И. Иммуногенетические факторы нейродегенеративных заболеваний: роль HLA II класса. Биохимия. 2018;83(9):1385–1398. [Aliseychik M.P., Andreeva T.V., Rogaev E.I. Immunogenetic factors of neurodegenerative diseases: the role of HLA class II. Biochemistry. 2018;83(9):1385–1398. (In Russ.)]. https://doi.org/10.1134/S0320972518090129
40. De Chiara G., Marcocci M.E., Sgarbanti R., Civitelli L., Ripoli C., Piacentini R. et al. Infectious agents and neurodegeneration. Mol. Neurobiol. 2012;46(3):614–38. https://doi.org/10.1007/s12035-012-8320-7
41. Tzeng N.S., Chung C.H., Lin F.H., Chiang C.P., Yeh C.B., Huang S.Y. et al. Anti-herpetic medications and reduced risk of dementia in patients with herpes simplex virus infections — a nationwide, population-based cohort study in Taiwan. Neurotherapeutics. 2018;15(2):417–29. https://doi.org/10.1007/s13311-018-0611-x
42. Mao L., Jin H., Wang M., Hu Y., Chen S., He Q. et al. Neurologic manifestations of hospitalized patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683–90. https://doi.org/10.1001/jamaneurol.2020.1127
43. Cheever F.S., Daniels J.B., Pappenheimer A.M., Bailey O.T. A murine virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin. J. Exp. Med. 1949;90(3):181– 210. https://doi.org/10.1084/jem.90.3.181
44. Alenina N., Bader M. ACE2 in brain physiology and pathophysiology: evidence from transgenic animal models. Neurochem. Res. 2019;44(6):1323–29. https://doi.org/10.1007/s11064-018-2679-4
45. Heurich A., Hofmann-Winkler H., Gierer S., Liepold T., Jahn O., Pöhlmann S. 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):1293–307. https://doi.org/10.1128/jvi.02202-13
46. Chen Z., Mi L., Xu J., Yu J., Wang X., Jiang J. et al. Function of HAb18G/ CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus. J. Infect. Dis. 2005;191(5):755–60. https://doi.org/10.1086/427811
47. Baig A.M., Khaleeq A., Ali U., Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neurosci. 2020;11(7):995–8. https://doi.org/10.1021/acschemneuro.0c00122
48. Bender S.J., Phillips J.M., Scott E.P., Weiss S.R. 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):11030–44. https://doi.org/10.1128/jvi.02688-09
49. Finsterer J., Stollberger C. Update on the neurology of COVID-19. J. Med. Virol. 2020;92(11):2316–8. https://doi.org/10.1002/jmv.26000
50. Kumar A., Pareek V., Prasoon P., Faiq M.A., Kumar P., Kumari C. 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):2376–83. https://doi.org/10.1002/jnr.24717
51. Najjar S., Najjar A., Chong D.J., Pramanik B.K., Kirsch C., Kuzniecky R.I. et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiologyand case reports. J. Neuroinflammation. 2020;17(1):231. https://doi.org/10.1186/s12974-020-01896-0
52. Zubair A.S., McAlpine L.S., Gardin T., Farhadian S., Kuruvilla D.E., Spudich S. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of Coronavirus Disease 2019. JAMA Neurol. 2020;77(8):1018–27. https://doi.org/10.1001/jamaneurol.2020.2065
53. Plog B.A., Nedergaard M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol. 2018;13(1):379–94. https://doi.org/10.1146/annurev-pathol-051217-111018
54. Netland J., Meyerholz D.K., Moore S., Cassell M., Perlman S. 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):7264–75. https://doi.org/10.1128/jvi.00737-08
Review
For citations:
Litvinenko I.V., Lobzin V.Yu., Pushkarev V.A., Skripchenko N.V. Infectious hypothesis of neurodegenerative diseases. What waits us after the COVID-19 pandemic? Russian neurological journal. 2022;27(3):64-73. (In Russ.) https://doi.org/10.30629/2658-7947-2022-27-3-64-73
Views:
735
Email this article 