Abstract
Alzheimer’s disease (AD) is a multifactorial disorder; neurofibrillary pathology composed of tau protein is found side by side with amyloid-β deposits and extensive neuroinflammation. The immune system of the brain is considered as one of the factors that could influence the speed of the progression of AD neuropathology as a potential mediator of the damage induced by AD protein deposits. Alzheimer’s disease pathology can be impacted by psychological stress; however, signalling pathways in background are not well known. We have explored possible avenues of how stress could influence the brain’s immune system in a rat model of AD. Animals were subjected either to a single or multiple instances of immobilization stress. The analysis of a panel of immunity-related genes was used to evaluate the impact of stress on the immune response in the brain. We have identified 19 stress-responsive genes that are involved in neuroinflammation accompanying tau pathology: Nos2, Ptgs2, IL-8rb, C5, Mmp9, Cx3cr1, CD40lg, Adrb2, IL-6, IL-6r, IL-1r2, Ccl2, Ccl3, Ccl4, Ccl12, TNF-α, IL-1α, IL-1β, IL-10. Most of them are deregulated under the stress conditions also in control animals; however, the magnitude of the response to either acute or chronic stress differs. This can lead to serious influence, most probably to acceleration of neurodegenerative phenotype in diseased animals. Several of the genes (IL-1β, Casp1, Cx3cr1 and C5) are deregulated solely in tauopathic animals. The stress-induced changes in the inflammatory picture of the brain highlight the fact that the brain’s immune response is highly responsive to environmental stimuli. The pattern of changes is indicative of an attempt to protect the brain in the short term, while being potentially detrimental to the response against a long-term pathological process such as neurofibrillary degeneration.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ader R (2000) On the development of psychoneuroimmunology. Eur J Pharmacol 405:167–176
Alafuzoff I et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484–496. doi:10.1111/j.1750-3639.2008.00147.x
Artemiadis AK, Anagnostouli MC, Alexopoulos EC (2011) Stress as a risk factor for multiple sclerosis onset or relapse: a systematic review. Neuroepidemiology 36:109–120. doi:10.1159/000323953
Ashutosh et al (2011) CXCL8 protects human neurons from amyloid-beta-induced neurotoxicity: relevance to Alzheimer’s disease. Biochem Biophys Res Commun 412:565–571. doi:10.1016/j.bbrc.2011.07.127
Avitsur R, Powell N, Padgett DA, Sheridan JF (2009) Social Interactions, Stress, and Immunity. Immunol Allergy Clin North Am 29:285–293. doi:10.1016/j.iac.2009.02.006
Bentham P, Gray R, Sellwood E, Hills R, Crome P, Raftery J (2008) Aspirin in Alzheimer’s disease (AD2000): a randomised open-label trial. Lancet Neurol 7:41–49. doi:10.1016/S1474-4422(07)70293-4
Benveniste EN, Nguyen VT, Wesemann DR (2004) Molecular regulation of CD40 gene expression in macrophages and microglia. Brain Behav Immun 18:7–12
Bettelli E et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238. doi:10.1038/nature04753
Borella P, Bargellini A, Rovesti S, Pinelli M, Vivoli R, Solfrini V, Vivoli G (1999) Emotional stability, anxiety, and natural killer activity under examination stress. Psychoneuroendocrinology 24:613–627
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta neuropathologica 82:239–259
Braak H, Braak E (1996) Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol 92:197–201
Brandes N, Schmitt S, Jakob U (2009) Thiol-based redox switches in eukaryotic proteins. Antioxid Redox Signal 11:997–1014. doi:10.1089/ARS.2008.2285
Buchanan JB, Sparkman NL, Chen J, Johnson RW (2008) Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 33:755–765. doi:10.1016/j.psyneuen.2008.02.013
Buchanan MM, Hutchinson M, Watkins LR, Yin H (2010) Toll-like receptor 4 in CNS pathologies. J Neurochem 114:13–27. doi:10.1111/j.1471-4159.2010.06736.x
Calderon-Garciduenas L et al (2013) Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrP(C)), Interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution. Front in Neuroscience 7:183. doi:10.3389/fnins.2013.00183
Cente M, Filipcik P, Pevalova M, Novak M (2006) Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J Neurosci 24:1085–1090. doi:10.1111/j.1460-9568.2006.04986.x
Cente M, Filipcik P, Mandakova S, Zilka N, Krajciova G, Novak M (2009) Expression of a truncated human tau protein induces aqueous-phase free radicals in a rat model of tauopathy: implications for targeted antioxidative therapy Journal of Alzheimer’s disease 17:913–920. doi:10.3233/JAD-2009-1107
Chang SY, Su PF, Lee TC (2009) Ectopic expression of interleukin-1 receptor type II enhances cell migration through activation of the pre-interleukin 1alpha pathway. Cytokine 45:32–38. doi:10.1016/j.cyto.2008.10.013
Colton CA et al (2006) NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 103:12867–12872. doi:10.1073/pnas.0601075103
Dafnis I, Tzinia AK, Tsilibary EC, Zannis VI, Chroni A (2012) An apolipoprotein E4 fragment affects matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1 and cytokine levels in brain cell lines. Neuroscience. doi:10.1016/j.neuroscience.2012.03.013
Davidson DC, Hirschman MP, Sun A, Singh MV, Kasischke K, Maggirwar SB (2012) Excess soluble CD40L contributes to blood brain barrier permeability in vivo: implications for HIV-associated neurocognitive disorders. PLoS ONE 7:e51793. doi:10.1371/journal.pone.0051793
de Brouwer SJM et al (2010) Experimental stress in inflammatory rheumatic diseases: a review of psychophysiological stress responses. Arthritis Research & Therapy 12:R89. doi:10.1186/ar3016
DeRijk RH, de Kloet ER (2008) Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience. Eur J Pharmacol 583:303–311. doi:10.1016/j.ejphar.2007.11.072
Dickerson SS, Gable SL, Irwin MR, Aziz N, Kemeny ME (2009) Social-evaluative threat and proinflammatory cytokine regulation: an experimental laboratory investigation. Psychol SCI 20:1237–1244. doi:10.1111/j.1467-9280.2009.02437.x
Duncan DS, Miller SD (2011) CNS expression of B7-H1 regulates pro-inflammatory cytokine production and alters severity of Theiler’s virus-induced demyelinating disease. PLoS ONE 6:e18548. doi:10.1371/journal.pone.0018548
Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36. doi:10.1007/s00401-009-0532-1
Eikelenboom P, Veerhuis R, van Exel E, Hoozemans JJ, Rozemuller AJ, van Gool WA (2011) The early involvement of the innate immunity in the pathogenesis of late-onset Alzheimer’s disease: neuropathological, epidemiological and genetic evidence. Curr Alzheimer Res 8:142–150
Entringer S, Kumsta R, Nelson EL, Hellhammer DH, Wadhwa PD, Wüst S (2008) Influence of prenatal psychosocial stress on cytokine production in adult women. Dev Psychobiol 50:579–587. doi:10.1002/dev.20316
Ferri CP et al (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–2117. doi:10.1016/S0140-6736(05)67889-0
Fireman E, Kraiem Z, Sade O, Greif J, Fireman Z (2002) Induced sputum-retrieved matrix metalloproteinase 9 and tissue metalloproteinase inhibitor 1 in granulomatous diseases. Clin Exp Immunol 130:331–337
Gaab J, Rohleder N, Heitz V, Engert V, Schad T, Schürmeyer TH, Ehlert U (2005) Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology 30:188–198. doi:10.1016/j.psyneuen.2004.06.008
Gadient RA, Otten UH (1997) Interleukin-6 (IL-6)–a molecule with both beneficial and destructive potentials. Prog Neurobiol 52:379–390
Gardiner J, Barton D, Overall R, Marc J (2009) Neurotrophic support and oxidative stress: converging effects in the normal and diseased nervous system. Neuroscientist 15:47–61. doi:10.1177/1073858408325269
Gebicke-Haerter PJ (2001) Microglia in neurodegeneration: molecular aspects. Microsc Res Tech 54:47–58. doi:10.1002/jemt.1120
Gerber JS, Mosser DM (2001) Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors. J Immunol 166:6861–6868
Goshen I et al (2007) A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32:1106–1115. doi:10.1016/j.psyneuen.2007.09.004
Harrison J et al (2014) Cognition in MCI and Alzheimer’s disease: baseline data from a longitudinal study of the NTB The Clinical neuropsychologist 28:252–268. doi:10.1080/13854046.2013.875595
Hayes A et al (2004) A polymorphic variation in the interleukin 1A gene increases brain microglial cell activity in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75:1475–1477. doi:10.1136/jnnp.2003.030866
Heneka MT et al (2010) Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107:6058–6063. doi:10.1073/pnas.0909586107
Heneka MT et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405. doi:10.1016/S1474-4422(15)70016-5
Ihara Y, Morishima-Kawashima M, Nixon R (2012) The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease. Cold Spring Harbor Perspect Med 2. doi:10.1101/cshperspect.a006361
Iqbal K, Liu F, Gong CX, Grundke-Iqbal I (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7:656–664
Irwin MR (2008) Human psychoneuroimmunology: 20 years of discovery brain. Behav Immun 22:129–139. doi:10.1016/j.bbi.2007.07.013
Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ (2009) Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci USA 106:14063–14068. doi:10.1073/pnas.0900096106
Kim SM et al (2011) Identification of peripheral inflammatory markers between normal control and Alzheimer’s disease. BMC neurol 11:51. doi:10.1186/1471-2377-11-51
Kinsey SG, Bailey MT, Sheridan JF, Padgett DA, Avitsur R (2007) Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL/6 and CD-1 mice. Brain Behav Immun 21:458–466. doi:10.1016/j.bbi.2006.11.001
Kinsey SG, Bailey MT, Sheridan JF, Padgett DA (2008) The inflammatory response to social defeat is increased in older mice. Physiol Behav 93:628–636. doi:10.1016/j.physbeh.2007.11.003
Koson P et al (2008) Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. Eur J Neurosci 28:239–246. doi:10.1111/j.1460-9568.2008.06329.x
Lathe R (2001) Hormones and the hippocampus J Endocrinol 169:205–231
Lejavova K et al (2015) Stress-induced activation of the sympathoadrenal system is determined by genetic background in rat models of tauopathy. J Alzheimer’s dis 43:1157–1161. doi:10.3233/JAD-141329
Maes M et al (2008) The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24:27–53. doi:10.1007/s11011-008-9118-1
Man SM et al (2007) Peripheral T cells overexpress MIP-1alpha to enhance its transendothelial migration in Alzheimer’s disease. Neurobiol Aging 28:485–496. doi:10.1016/j.neurobiolaging.2006.02.013
Maolood N, Hardin-Pouzet H, Grange-Messent V (2008) Matrix metalloproteinases MMP2 and MMP9 are upregulated by noradrenaline in the mouse neuroendocrine hypothalamus. Eur J Neurosci 27:1143–1152. doi:10.1111/j.1460-9568.2008.06099.x
Mattila KM, Rinne JO, Lehtimaki T, Roytta M, Ahonen JP, Hurme M (2002) Association of an interleukin 1B gene polymorphism (-511) with Parkinson’s disease in Finnish patients. J Med Genet 39:400–402
Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639. doi:10.1038/nature02621
Mausbach BT et al (2008) A 5-year longitudinal study of the relationships between stress, coping, and immune cell β2-adrenergic receptor sensitivity. Psychiatry Res 160:247–255. doi:10.1016/j.psychres.2007.09.006
McCoy MK, Tansey MG (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5:45. doi:10.1186/1742-2094-5-45
McKhann GM et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dementia 7:263–269. doi:10.1016/j.jalz.2011.03.005
Moore AH et al (2010) Non-steroidal anti-inflammatory drugs in alzheimer’s disease and Parkinson’s disease: Reconsidering the Role of Neuroinflammation. Pharmaceuticals 3:1812–1841. doi:10.3390/ph3061812
Motulsky H (2010) Intuitive biostatistics: a nonmathematical guide to statistical thinking. Completely rev, 2nd edn. Oxford University Press, New York
Mravec B, Vargovic P, Filipcik P, Novak M, Kvetnansky R (2015) Effect of a single and repeated stress exposure on gene expression of catecholamine biosynthetic enzymes in brainstem catecholaminergic cell groups in rats. Eur J Neurosci 42:1872–1886. doi:10.1111/ejn.12955
Mravec B et al (2016) Tauopathy in transgenic (SHR72) rats impairs function of central noradrenergic system and promotes neuroinflammation. J Neuroinflammation 13:15. doi:10.1186/s12974-016-0482-1
Mukaino M et al (2010) Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation. Exp Neurol 224:403–414. doi:10.1016/j.expneurol.2010.04.020
Murase S, McKay RD (2012) Matrix Metalloproteinase9 Regulates Survival of Neurons in Newborn Hippocampus. J biol chem. doi:10.1074/jbc.M111.297671
Nelson PT et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381. doi:10.1097/NEN.0b013e31825018f7
Park KM, Bowers WJ (2010) Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 22:977–983. doi:10.1016/j.cellsig.2010.01.010
Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201. doi:10.1038/nrneurol.2010.17
Pompl PN et al (2003) Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Arch Neurol 60:369–376
Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer disease Nature reviews, Neurology 7:137–152. doi:10.1038/nrneurol.2011.2
Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11:785–797. doi:10.1038/ni.1923
Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181. doi:10.1038/nri2711
Schutyser E, Struyf S, Van Damme J (2003) The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev 14:409–426
Sciacca FL et al (2003) Interleukin-1B polymorphism is associated with age at onset of Alzheimer’s disease. Neurobiol Aging 24:927–931
Serretti A, Olgiati P, De Ronchi D (2007) Genetics of Alzheimer’s disease. A rapidly evolving field. J Alzheimer’s dis 12:73–92
Sokolowski JD, Chabanon-Hicks CN, Han CZ, Heffron DS, Mandell JW (2014) Fractalkine is a “find-me” signal released by neurons undergoing ethanol-induced apoptosis. Frontiers Cellular Neuroscience 8:360. doi:10.3389/fncel.2014.00360
Solovjov DA, Pluskota E, Plow EF (2005) Distinct roles for the alpha and beta subunits in the functions of integrin alphaMbeta2. T J Biol Chem 280:1336–1345. doi:10.1074/jbc.M406968200
Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12:609–622. doi:10.1016/S1474-4422(13)70090-5
Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, Gerlo S (2011) Interleukin-6, a mental cytokine. Brain Res Rev 67:157–183. doi:10.1016/j.brainresrev.2011.01.002
Spulber S, Schultzberg M (2010) Connection between inflammatory processes and transmittor function-Modulatory effects of interleukin-1. Prog Neurobiol 90:256–262. doi:10.1016/j.pneurobio.2009.10.015
Spulber S, Bartfai T, Schultzberg M (2009) IL-1/IL-1ra balance in the brain revisited—evidence from transgenic mouse models. Brain Behav Immun 23:573–579. doi:10.1016/j.bbi.2009.02.015
Stark JL, Avitsur R, Padgett DA, Campbell KA, Beck FM, Sheridan JF (2001) Social stress induces glucocorticoid resistance in macrophages. Am J Physiol Regulatory Integr Comp Physiol 280:R1799–R1805
Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054–1059. doi:10.1038/nature04671
Stozicka Z, Zilka N, Novak P, Kovacech B, Bugos O, Novak M (2010a) Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer’s disease. J Neuroinflammation 7:64. doi:10.1186/1742-2094-7-64
Stozicka Z, Zilka N, Novak P, Kovacech B, Bugos O, Novak M (2010b) Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer’s disease. J Neuroinflammation 7:64. doi:10.1186/1742-2094-7-64
Tabor-Godwin JM et al (2010) A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS. J Neurosci 30:8676–8691. doi:10.1523/JNEUROSCI.1860-10.2010
Tsang AH, Chung KK (2009) Oxidative and nitrosative stress in Parkinson’s disease. Biochem Biophys Acta 1792:643–650. doi:10.1016/j.bbadis.2008.12.006
Vambutas A, DeVoti J, Goldofsky E, Gordon M, Lesser M, Bonagura V (2009) Alternate splicing of interleukin-1 receptor type II (IL1R2) in vitro correlates with clinical glucocorticoid responsiveness in patients with AIED. PLoS ONE 4:e5293. doi:10.1371/journal.pone.0005293
Veerhuis R, Nielsen HM, Tenner AJ (2011) Complement in the brain. Mol Immunol 48:1592–1603. doi:10.1016/j.molimm.2011.04.003
Villa P et al (2007) The interleukin-8 (IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-term inflammation in permanent and transient cerebral ischemia in rats. Mol Med 13:125–133. doi:10.2119/2007-00008.Villa
Wellek S (2003) Testing statistical hypotheses of equivalence. Chapman & Hall/CRC, Boca Raton
Welsh CJ et al (2010) Effects of stress on the immune response to Theiler’s virus–implications for virus-induced autoimmunity. NeuroImmunoModulation 17:169–172. doi:10.1159/000258715
Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S, Hansson O (2012) CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLoS ONE 7:e30525. doi:10.1371/journal.pone.0030525
Wilson CJ, Finch CE, Cohen HJ (2002) Cytokines and cognition–the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 50:2041–2056
Wimo A et al (2011) The economic impact of dementia in Europe in 2008-cost estimates from the Eurocode project. Int J Geriatr Psychiatry 26:825–832. doi:10.1002/gps.2610
Zanjani H, Finch CE, Kemper C, Atkinson J, McKeel D, Morris JC, Price JL (2005) Complement activation in very early Alzheimer disease. Alzheimer Dis Assoc Disord 19:55–66
Zhang Y, Miao J, Hanley G, Stuart C, Sun X, Chen T, Yin D (2008) Chronic restraint stress promotes immune suppression through toll-like receptor 4-mediated phosphoinositide 3-kinase signaling. J Neuroimmunol 204:13–19. doi:10.1016/j.jneuroim.2008.08.011
Zilka N et al (2006) Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett 580:3582–3588. doi:10.1016/j.febslet.2006.05.029
Zilka N, Stozicka Z, Kovac A, Pilipcinec E, Bugos O, Novak M (2009) Human misfolded truncated tau protein promotes activation of microglia and leukocyte infiltration in the transgenic rat model of tauopathy. J Neuroimmunol 209:16–25. doi:10.1016/j.jneuroim.2009.01.013
Zilka N et al (2012a) Who fans the flames of Alzheimer’s disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways. J Neuroinflammation 9:47. doi:10.1186/1742-2094-9-47
Zilka N, Stozicka Z, Cente M, Kazmerova Z, Kovacech B, Novak M (2012b) Immunomodulation of memory-impairing protein tau in Alzheimer’s disease. Neuro-degenerative Dis. doi:10.1159/000333125
Zou JY, Crews FT (2005) TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res 1034:11–24. doi:10.1016/j.brainres.2004.11.014
Acknowledgements
This work was supported by the grants from research funding agencies of Slovak Republic: APVV-0677-12; VEGA 2/0194/14; VEGA 2/0141/15 and VEGA 2/0147/16.
Author information
Authors and Affiliations
Contributions
RK, MN, PF designed experiments; PN, TA performed stress experiments; MC, NK performed transcriptomic analyses; PN, MC, PF analysed data, organized research and wrote a manuscript.
Corresponding author
Ethics declarations
Conflicts of interest
The authors have no conflicts of interest to declare.
Ethical statement
All experiments were performed in accordance to the Slovak and European Community Guidelines, with the approval of Ethical Committee the Institute of Neuroimmunology and State Veterinary and Food Administration of the Slovak Republic; approval No. Ro-2534/12-221.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Novak, P., Cente, M., Kosikova, N. et al. Stress-Induced Alterations of Immune Profile in Animals Suffering by Tau Protein-Driven Neurodegeneration. Cell Mol Neurobiol 38, 243–259 (2018). https://doi.org/10.1007/s10571-017-0491-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-017-0491-3