Abstract
Patients affected by COVID-19 present mostly with respiratory symptoms but acute neurological symptoms are also commonly observed. Furthermore, a considerable number of individuals develop persistent and often remitting symptoms months after infection, characterizing the condition called long-COVID. Since the pathophysiology of acute and persistent neurological manifestations is not fully established, we evaluated the expression of different genes in hippocampal slices of aged rats exposed to the serum of a post-COVID (sPC) individual and to the serum of patients infected by SARS-CoV-2 [Zeta (sZeta) and Gamma (sGamma) variants]. The expression of proteins related to inflammatory process, redox homeostasis, mitochondrial quality control and glial reactivity was determined. Our data show that the exposure to sPC, sZeta and sGamma differentially altered the mRNA levels of most inflammatory proteins and reduced those of antioxidant response markers in rat hippocampus. Furthermore, a decrease in the expression of mitochondrial biogenesis genes was induced by all serum samples, whereas a reduction in mitochondrial dynamics was only caused by sPC. Regarding the glial reactivity, S100B expression was modified by sPC and sZeta. These findings demonstrate that changes in the inflammatory response and a reduction of mitochondrial biogenesis and dynamics may contribute to the neurological damage observed in COVID-19 patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
Data will be made available upon request.
References
Alvarez-Guardia D, Palomer X, Coll T, Davidson MM, Chan TO, Feldman AM, Laguna JC, Vázquez-Carrera M (2010) The p65 subunit of NF-kappaB binds to PGC-1alpha, linking inflammation and metabolic disturbances in cardiac cells. Cardiovasc Res 87(3):449–458. https://doi.org/10.1093/cvr/cvq080
Angelopoulou E, Paudel YN, Piperi C (2021) Emerging role of S100B protein implication in Parkinson’s disease pathogenesis. Cell Mol Life Sci CMLS 78(4):1445–1453. https://doi.org/10.1007/s00018-020-03673-x
Banoth B, Cassel SL (2018) Mitochondria in innate immune signaling. Translational Research. J Lab Clin Med 202:52–68. https://doi.org/10.1016/j.trsl.2018.07.014
Bartsch T, Wulff P (2015) The hippocampus in aging and disease: From plasticity to vulnerability. Neuroscience 309:1–16. https://doi.org/10.1016/j.neuroscience.2015.07.084
Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC (2002) Control of synaptic strength by glial TNFalpha. Science (New York, N.Y.), 295(5563):2282–2285. https://doi.org/10.1126/science.1067859
Bhowal C, Ghosh S, Ghatak D, De R (2022) Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight. Mol cell biochem 1–19. Advance online publication. https://doi.org/10.1007/s11010-022-04593-z
Bobermin LD, Quincozes-Santos A, Santos CL, Varela APM, Teixeira TF, Wartchow KM, Lissner LJ, da Silva A, Thomaz NK, Santi L, Beys-da-Silva WO, Roehe PM, Sesterheim P, Guimarães JA, Gonçalves CA, Souza DO (2020) Zika virus exposure affects neuron-glia communication in the hippocampal slices of adult rats. Sci Rep 10(1):21604. https://doi.org/10.1038/s41598-020-78735-y
Bousquet J, Cristol JP, Czarlewski W, Anto JM, Martineau A, Haahtela T, Fonseca SC, Iaccarino G, Blain H, Fiocchi A, Canonica GW, Fonseca JA, Vidal A, Choi HJ, Kim HJ, Le Moing V, Reynes J, Sheikh A, Akdis CA, Zuberbier T, ARIA group (2020) Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies. Clin transl allergy 10(1):58. https://doi.org/10.1186/s13601-020-00362-7
Burtscher J, Cappellano G, Omori A, Koshiba T, Millet GP (2020) Mitochondria: In the Cross Fire of SARS-CoV-2 and Immunity. iScience 23(10):101631. https://doi.org/10.1016/j.isci.2020.101631
Carty M, Bowie AG (2010) Recent insights into the role of Toll-like receptors in viral infection. Clin Exp Immunol 161(3):397–406. https://doi.org/10.1111/j.1365-2249.2010.04196.x
Chen Y, Guo S, Tang Y, Mou C, Hu X, Shao F, Yan W, Wu Q (2020) Mitochondrial Fusion and Fission in Neuronal Death Induced by Cerebral Ischemia-Reperfusion and Its Clinical Application: A Mini-Review. Medical science monitor: Int Med J Experimen Clin Res 26:e928651. https://doi.org/10.12659/MSM.928651
Chen Z, Li G (2021) Immune response and blood-brain barrier dysfunction during viral neuroinvasion. Innate Immun 27(2):109–117. https://doi.org/10.1177/1753425920954281
Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, Cotman CW (2012) Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation 9:179. https://doi.org/10.1186/1742-2094-9-179
Crunfi F et al (2020) SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability. medRxiv. https://doi.org/10.1101/2020.10.09.20207464
Dresselhaus EC, Meffert MK (2019) Cellular Specificity of NF-κB Function in the Nervous System. Front Immunol 10:1043. https://doi.org/10.3389/fimmu.2019.01043
Fang D, Maldonado EN (2018) VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation. Adv Cancer Res 138:41–69. https://doi.org/10.1016/bs.acr.2018.02.002
Faria NR, Mellan TA, Whittaker C, Claro IM, Candido DDS, Mishra S, Crispim MAE, Sales FCS, Hawryluk I, McCrone JT, Hulswit RJG, Franco LAM, Ramundo MS, de Jesus JG, Andrade PS, Coletti TM, Ferreira GM, Silva CAM, Manuli ER, Pereira RHM, Sabino EC (2021) Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science 372(6544):815–821. https://doi.org/10.1126/science.abh2644
Gümüş H, Erat T, Öztürk İ, Demir A, Koyuncu I (2022) Oxidative stress and decreased Nrf2 level in pediatric patients with COVID-19. J Med Virol 94(5):2259–2264. https://doi.org/10.1002/jmv.27640
Halpin S, O’Connor R, Sivan M (2021) Long COVID and chronic COVID syndromes. J Med Virol 93(3):1242–1243. https://doi.org/10.1002/jmv.26587
Hosseini S, Michaelsen-Preusse K, Schughart K, Korte M (2021) Long-Term Consequence of Nonneurotropic H3N2 Influenza A Virus Infection for the Progression of Alzheimer's Disease Symptoms. Front Cell Neurosci 15:643650. https://doi.org/10.3389/fncel.2021.643650
Kanberg N, Ashton NJ, Andersson LM, Yilmaz A, Lindh M, Nilsson S, Price RW, Blennow K, Zetterberg H, Gisslén M (2020) Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology 95(12):e1754–e1759. https://doi.org/10.1212/WNL.0000000000010111
Kang SJ, Jung SI (2020) Age-Related Morbidity and Mortality among Patients with COVID-19. Infect Chemother 52(2):154–164. https://doi.org/10.3947/ic.2020.52.2.154
Kim BS, Jin YH, Meng L, Hou W, Kang HS, Park HS, Koh CS (2012) IL-1 signal affects both protection and pathogenesis of virus-induced chronic CNS demyelinating disease. J Neuroinflammation 9:217. https://doi.org/10.1186/1742-2094-9-217
Khan H, Patel S, Majumdar A (2021) Role of NRF2 and Sirtuin activators in COVID-19. Clin Immun (Orlando, Fla.) 233:108879. https://doi.org/10.1016/j.clim.2021.108879
Kokkoris S, Stamataki E, Emmanouil G, Psachoulia C, Ntaidou T, Maragouti A, Kanavou A, Malachias S, Christodouli F, Papachatzakis I, Markaki V, Katsaros D, Vasileiadis I, Glynos C, Routsi C (2022) Serum inflammatory and brain injury biomarkers in COVID-19 patients admitted to intensive care unit: A pilot study. eNeurological Sci, 29:100434. https://doi.org/10.1016/j.ensci.2022.100434
Kraner SD, Norris CM (2018) Astrocyte Activation and the Calcineurin/NFAT Pathway in Cerebrovascular Disease. Front Aging Neurosci 10:287. https://doi.org/10.3389/fnagi.2018.00287
Lowery SA, Sariol A, Perlman S (2021) Innate immune and inflammatory responses to SARS-CoV-2: Implications for COVID-19. Cell Host Microbe 29(7):1052–1062. https://doi.org/10.1016/j.chom.2021.05.004
Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426. https://doi.org/10.1146/annurev-pharmtox-011112-140320
Mitchell S, Vargas J, Hoffmann A (2016) Signaling via the NFκB system. Wiley Interdiscipl Rev Syst Biol Med 8(3):227–241. https://doi.org/10.1002/wsbm.1331
Monje M, Iwasaki A (2022) The neurobiology of long COVID. Neuron 110(21):3484–3496. https://doi.org/10.1016/j.neuron.2022.10.006
Mueller AL, McNamara MS, Sinclair DA (2020) Why does COVID-19 disproportionately affect older people. Aging 12(10):9959–9981. https://doi.org/10.18632/aging.103344
Najjar S, Najjar A, Chong DJ, Pramanik BK, Kirsch C, Kuzniecky RI, Pacia SV, Azhar S (2020) Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflammation 17(1):231. https://doi.org/10.1186/s12974-020-01896-0
Nardin P, Tortorelli L, Quincozes-Santos A, de Almeida LM, Leite MC, Thomazi AP, Gottfried C, Wofchuk ST, Donato R, Gonçalves CA (2009) S100B secretion in acute brain slices: modulation by extracellular levels of Ca(2+) and K (+). Neurochem Res 34(9):1603–1611. https://doi.org/10.1007/s11064-009-9949-0
Nasserie T, Hittle M, Goodman SN (2021) Assessment of the Frequency and Variety of Persistent Symptoms Among Patients With COVID-19: JAMA network open. Syst Rev 4(5):e2111417. https://doi.org/10.1001/jamanetworkopen.2021.11417
Nguyen T, Di Giovanni S (2008) NFAT signaling in neural development and axon growth: the Official Journal of the International Society for Developmental Neuroscience. Int J Dev Neurosci 26(2):141–145. https://doi.org/10.1016/j.ijdevneu.2007.10.004
Olagnier D, Farahani E, Thyrsted J, Blay-Cadanet J, Herengt A, Idorn M, Hait A, Hernaez B, Knudsen A, Iversen MB, Schilling M, Jørgensen SE, Thomsen M, Reinert LS, Lappe M, Hoang HD, Gilchrist VH, Hansen AL, Ottosen R, Nielsen CG, Holm CK (2020) SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nature Commun 11(1):4938. https://doi.org/10.1038/s41467-020-18764-3
Orzalli MH, Smith A, Jurado KA, Iwasaki A, Garlick JA, Kagan JC (2018) An Antiviral Branch of the IL-1 Signaling Pathway Restricts Immune-Evasive Virus Replication. Mol Cell 71(5):825-840.e6. https://doi.org/10.1016/j.molcel.2018.07.009
Quincozes-Santos A, Rosa RL, Tureta EF, Bobermin LD, Berger M, Guimarães JA, Santi L, Beys-da-Silva WO (2021) COVID-19 impacts the expression of molecular markers associated with neuropsychiatric disorders. Brain Behav Immun Health 11: 100196. https://doi.org/10.1016/j.bbih.2020.100196
Raveendran AV, Jayadevan R, Sashidharan S (2021) Long COVID: An overview. Diabetes Metab Syndr15(3):869–875. https://doi.org/10.1016/j.dsx.2021.04.007
Santello M, Bezzi P, Volterra A (2011) TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69(5):988–1001. https://doi.org/10.1016/j.neuron.2011.02.003
Sanz P, Garcia-Gimeno MA (2020) Reactive Glia Inflammatory Signaling Pathways and Epilepsy. Int J Mol Sci 21(11):4096. https://doi.org/10.3390/ijms21114096
Seminotti B, Grings M, Tucci P, Leipnitz G, Saso L (2021) Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders. Front Cell Neurosci 15:785057. https://doi.org/10.3389/fncel.2021.785057
Shivarama Shetty M, Sajikumar S (2017) “Tagging” along memories in aging: Synaptic tagging and capture mechanisms in the aged hippocampus. Ageing Res Rev 35:22–35. https://doi.org/10.1016/j.arr.2016.12.008
Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N (2010) VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med 31(3):227–285. https://doi.org/10.1016/j.mam.2010.03.002
Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Iwasaki A (2021) Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exptl Med 218(3):e20202135. https://doi.org/10.1084/jem.20202135
Spudich S, Nath A (2022) Nervous system consequences of COVID-19. Science (New York, N.Y.) 375(6578):267–269. https://doi.org/10.1126/science.abm2052
Stellwagen D, Beattie EC, Seo JY, Malenka RC (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha: the Official Journal of the Society for Neuroscience. J Neurosci 25(12):3219–3228. https://doi.org/10.1523/JNEUROSCI.4486-04.2005
Subramanian A, Nirantharakumar K, Hughes S, Myles P, Williams T, Gokhale KM, Taverner T, Chandan JS, Brown K, Simms-Williams N, Shah AD, Singh M, Kidy F, Okoth K, Hotham R, Bashir N, Cockburn N, Lee SI, Turner GM, Gkoutos GV, Haroon S (2022) Symptoms and risk factors for long COVID in non-hospitalized adults. Nature Med 28(8):1706–1714. https://doi.org/10.1038/s41591-022-01909-w
Tamir H, Melamed S, Erez N, Politi B, Yahalom-Ronen Y, Achdout H, Lazar S, Gutman H, Avraham R, Weiss S, Paran N, Israely T (2022) Induction of Innate Immune Response by TLR3 Agonist Protects Mice against SARS-CoV-2 Infection. Viruses 14(2):189. https://doi.org/10.3390/v14020189
Tan Y, Zhang W, Zhu Z, Qiao N, Ling Y, Guo M, Yin T, Fang H, Xu X, Lu G, Zhang P, Yang S, Fu Z, Liang D, Xie Y, Zhang R, Jiang L, Yu S, Lu J, Jiang F, Chen S (2021) Integrating longitudinal clinical laboratory tests with targeted proteomic and transcriptomic analyses reveal the landscape of host responses in COVID-19. Cell Discov 7(1):42. https://doi.org/10.1038/s41421-021-00274-1
Thompson EA, Cascino K, Ordonez AA, Zhou W, Vaghasia A, Hamacher-Brady A, Brady NR, Sun IH, Wang R, Rosenberg AZ, Delannoy M, Rothman R, Fenstermacher K, Sauer L, Shaw-Saliba K, Bloch EM, Redd AD, Tobian AA, Horton M, Smith K, Powell JD (2020) Metabolic programs define dysfunctional immune responses in severe COVID-19 patients. preprint server for health sciences. medRxiv 2020.09.10.20186064. https://doi.org/10.1101/2020.09.10.20186064
Vabret N, Britton GJ, Gruber C, Hegde S, Kim J, Kuksin M, Levantovsky R, Malle L, Moreira A, Park MD, Pia L, Risson E, Saffern M, Salomé B, Esai Selvan M, Spindler MP, Tan J, van der Heide V, Gregory JK, Alexandropoulos K (2020) Sinai Immunology Review Project Immunology of COVID-19: Current State of the Science. Immunity 52(6):910–941. https://doi.org/10.1016/j.immuni.2020.05.002
van der Horst D, Carter-Timofte ME, van Grevenynghe J, Laguette N, Dinkova-Kostova AT, Olagnier D (2022) Regulation of innate immunity by Nrf2. Curr Opinion Immun 78:102247. https://doi.org/10.1016/j.coi.2022.102247
Varela APM, Prichula J, Mayer FQ, Salvato RS, Sant’Anna FH, Gregianini TS, Martins LG, Seixas A, Veiga ABGD (2021) SARS-CoV-2 introduction and lineage dynamics across three epidemic peaks in Southern Brazil: Massive spread of P.1. Infect. Genet Evol 96:105144
Voloch CM, da Silva Francisco R, Jr de Almeida LGP, Cardoso CC, Brustolini OJ, Gerber AL, Guimarães APC, Mariani D, da Costa RM, Ferreira OC, Jr, Adriana Cony Cavalcanti, Frauches TS, de Mello CMB, Leitão IC, Galliez RM, Faffe DS, Castiñeiras TMPP, Tanuri A, de Vasconcelos ATR (2021) Covid 19-UFRJ Workgroup, Genomic characterization of a novel SARS-CoV-2 lineage from Rio de Janeiro, Brazil. J Virol 95(10):e00119–21. https://doi.org/10.1128/JVI.00119-21. Advance Online Publication
von Bernhardi R, Tichauer JE, Eugenín J (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112(5):1099–1114. https://doi.org/10.1111/j.1471-4159.2009.06537.x
von Bettio LEB, Rajendran L, Gil-Mohapel J (2017) The effects of aging in the hippocampus and cognitive decline. Neurosci Biobehav Rev 79:66–86. https://doi.org/10.1016/j.neubiorev.2017.04.030
Vringer E, Tait SWG (2022) Mitochondria and cell death-associated inflammation. Cell Death Differ. https://doi.org/10.1038/s41418-022-01094-w. Advance Online Publication
Yong SJ, Yong MH, Teoh SL, Soga T, Parhar I, Chew J, Lim WL (2021) The Hippocampal Vulnerability to Herpes Simplex Virus Type I Infection: Relevance to Alzheimer's Disease and Memory Impairment. Front Cell Neurosci 15:695738. https://doi.org/10.3389/fncel.2021.695738
ZhangL, Zhou L, Bao L, Liu J, Zhu H, Lv Q, Liu R, Chen W, Tong W, Wei Q, Xu Y, Deng W, Gao H, Xue J, Song Z, Yu P, Han Y, Zhang Y, Sun X, Yu X, Qin C (2021) SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration. Signal transduct Tar Ther 6(1):337. https://doi.org/10.1038/s41392-021-00719-9
Zheng M, Karki R, Williams EP, Yang D, Fitzpatrick E, Vogel P, Jonsson CB, Kanneganti TD (2021) TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat Immunol 22(7):829–838. https://doi.org/10.1038/s41590-021-00937-x
Author information
Authors and Affiliations
Corresponding authors
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Montenegro, Y.H.A., Bobermin, L.D., Sesterheim, P. et al. Serum of COVID-19 patients changes neuroinflammation and mitochondrial homeostasis markers in hippocampus of aged rats. J. Neurovirol. 29, 577–587 (2023). https://doi.org/10.1007/s13365-023-01156-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-023-01156-w