Abstract
An important marker in Alzheimer disease (AD) is the abnormal production and accumulation of β-amyloid peptide (Aß) in brain. It produces oxidative damage in neurons and inflammation due to its neurotoxic properties. The present study was designed to investigate neuroinflammation (hippocampal levels of ROS, nitrite, TNF-α, and IL-1β), neurodegeneration (plaques and chromatolysis in hippocampus), and memory impairments (working memory and reference memory) and the effect of this neuroinflammation on some peripheral immunological parameters such as phagocytic activity of blood WBC and splenic polymorphonuclear (PMN) cells, leucocyte adhesion inhibition index (LAI), and cytotoxicity of splenic mononuclear cells (MNC) after the intracebroventricular injection of aggregated Aβ(1–42)in a 4week study. The results showed that the hippocampal and serum levels of ROS, nitrite, TNF-α, and IL-1β were significantly higher in the AD animals along with increased chromatolysis and impairments of memory. There was also a significant increase in the phagocytic activity of splenic PMN and cytotoxicity of splenic MNC and a decrease in the phagocytic activity of blood WBC and LAI of splenic MNC in the Aβ(1–42)-injected AD rats compared to that of control and sham-operated rats. The results indicate that the increased levels of inflammatory markers in the hippocampus may provide signals to the periphery and can alter the systemic immune responses.
Similar content being viewed by others
References
Akama KT, Van Eldik LJ (2000) β-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1b- and tumor necrosis factor-a (TNFa)-dependent, and involves a TNFa receptor-associated factor- and NFkB-inducing kinase-dependent signaling mechanism. J Biol Chem 275(11):7918–7924
Aloisi F (2001) Immune function of microglia. Glia 36:165–179
Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M (2007) Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging 28:533–536
Bertram L, Tanzi RE (2012) The genetics of alzheimer’s disease. Prog Mol Biol Transl Sci 107:79–100
Bowman GL, Kaye JA, Moore M, Waichunas D, Carlson NE, Quinn JF (2007) Blood-brain barrier impairment in Alzheimer disease: stability and functional significance. Neurology 68:1809–1814
Britschgi M, Wyss-Coray T (2007) Systemic and acquired immune responses in Alzheimer’s disease. Int Rev Neurobiol 82:205–233
Butterfield DA (1997) β-Amyloid-associated free radical oxidative stress and neurotoxicity : implications for Alzheimer’s disease. Chem Res Toxicol 10:495–506
Butterfield DA, Drake J, Pocernich C, Castegna A (2001) Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med 7:548–554
Butterfield DA, Swomley AM, Sultana R (2013) Amyloid β-peptide (1–42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 19(8):823–835. https://doi.org/10.1089/ars.2012.5027
Cetin F, Dincer S (2007) Effect of intrahippocampal beta amyloid (1-42) peptide injection on oxidant and antioxidant status in rat brain. Ann N Y Acad Sci 1100:510–517
Cetin F, Yazihan N, Dincer S, Akbulut G (2013) The effect of intracerebroventricular injection of BETA amyloid peptide (1-42) on caspase-3 activity, lipid peroxidation, nitric oxide and NOS expression in young adult and aged rat brain. Turk Neurosurg 23(2):144–150
Chabrier PE, Demerle-Pallardy C, Augnet M (1999) Nitric synthases: targets for therapeutic strategies in neurological diseases. Cell Mol Life Sci 55:1029–1035
Chen JH, Ke KF, Lu JH, Qiu YH, Peng YP (2015) Protection of TGF-β1 against neuroinflammation and neurodegeneration in Aβ1–42-induced Alzheimer’s disease model rats. PLoS One 10(2):e0116549. https://doi.org/10.1371/journal.pone.0116549
Ciaramella A, Salani F, Bizzoni F, Orfei MD, Caltagirone C, Spalletta G, Bossù P (2016) Myeloid dendritic cells are decreased in peripheral blood of Alzheimer’s disease patients in association with disease progression and severity of depressive symptoms. J Neuroinflammation 13:18. https://doi.org/10.1186/s12974-016-0483-0
Cioanca O, Hritcu L, Mihasana M, Hancianu M (2013) Cognitive-enhancing and antioxidant activities of inhaled coriander volatile oil in amyloid β (1–42) rat model of Alzheimer’s disease. Physiol Behav 120:193–202
Cox G (1977) Neuropathological techniques. In: Bancroft JD, Stevens A (eds) Theory and practice of histological techniques. Elsevier, London, pp 258–259
Craft JM, Watterson DM, Frautschy SA, Eldik LJ (2004) Aminopyridazines inhibit 훽-amyloid-induced glial activation and neuronal damage in vivo. Neurobiol Aging 25(10):1283–1292
Crimins JL, Pooler A, Polydoro M, Luebke JI, Spires-Jones TL (2013) The intersection of amyloid beta and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer’s disease. Ageing Res Rev 12(3):757–763
Csolle C, Sperlagh B (2010) Peripheral origin of IL-1β production in the rodent hippocampus under in vivo systemic bacterial lipoplysaccharide (LPS) challenge and it’s regulation by P2X7 receptors. J Neuroimmunol 219:38–46
Csölle C, Sperlagh B (2011) Endo-cannabinergic modulation of IL-1β in mouse hippo-campus under basal conditions and after in vivo systemic lipopolysaccharide stimulation. Neuroimmunomodulation 18:226–231
Davydova TV, Fomina VG, Voskresenskaya NI, Doronina OA (2003) Phagocytic activity and state of bactericidal systems in polymorphonuclear leukocytes from patients with Alzheimer’s disease. Bull Exp Biol Med 136:355–357
de Vries HE, Kuiper J, DeBoer AG, VanBerkel TJC, Breimer DD (1997) The blood-brain barrier in neuroinflammatory diseases. Pharmacol Rev 49:143–155
Diaz A, Limon D, Chavez R, Zenteno E, Guevara J (2012) Aβ25–35 injection into the temporal cortex induces chronic inflammation that contributes to neurodegeneration and spatial memory impairment in rats. J Alzheimers Dis 30(3):505–522
Diaz A, Rojas K, Espinosa B, Chavez R, Zenteno E, Limon D, Guevara J (2014) Aminoguanidine treatment ameliorates inflammatory responses and memory impairment induced by amyloid-beta 25–35 injection in rats. Neuropeptides 48:153–159
Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-Tur J et al (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713
Eftekharzadeh B, Ramin M, Khodagholi F, Moradi S, Tabrizian K, Sharif R et al (2012) Inhibition of PKA attenuates memory deficits induced by β-amyloid (1–42), and decreases oxidative stress and NF-κB transcription factors. Behav Brain Res 226:301–308
Frautschy SA, Cole GM, Baird A (1992) Phagocytosis and deposition of vascular β-amyloid in rat brains injected with Alzheimer β-amyloid. Am J Pathol 140(6):1389–1399
Garthwaite J, Garthwaite G, Palmer RMJ, Moncada S (1989) NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol 172:413–416
Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immune effector cell of the brain. Brain Res Rev 20:269–287
Goedert M, Spillantini MG (2006) A century of Alzheimer’s disease. Science 314:777–781
Golden N, Darmadipura S (2007) The role of microglia as prime component of CNS immune system in acute and chronic neuroinflammation. Folia Medica Indonesiana 43:54–58
Goulding NJ, Flower RJ (1997) Glucocorticoids and the immune system. In: Buckingham JC, Gillies GE, Cowell A (eds) Stress, stress hormone and the immune system, Jhon Wiley & Sons, Chichester, pp 199–223
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356
Hardy JA, Mann DM, Wester P, Winblad B (1986) An integrative hypothesis concerning the pathogenesis and progression of Alzheimer’s disease. Neurobiol Aging 7:489–502
Harkany T, De Jong GI, Soos K, Penke B, Luiten PG, Gulya K (1995) Beta amyloid (1-42) affects cholinergic but not parvalbumin-containing neurons in the septal complex of the rat. Brain Res 698:270–274
Harris ME, Hensley K, Butterfield DA, Leedle RA, Carney JM (1995) Direct evidence of oxidative injury by the Alzheimer’s amyloid peptide in cultured hippocampal neurons. Exp Neurol 131:193–202
Jhoo JH, Kim H-C, Nabeshima T, Yamada K, Shin E-J, Jhoo W-K, Kim W, Kang KS, Jo SA, Woo JI (2004) β-Amyloid (1–42)-induced learning and memory deficits in mice: involvement of oxidative burdens in the hippocampus and cerebral cortex. Behav Brain Res 155:185–196
Kalia M (2003) Dysphagia and aspiration pneumonia in patients with Alzheimer’s disease. Metabolism 52:36–38
Kaufman JC, Harris TJ, Higgins J, Maisel AS (1994) Exercise-induced enhancement of immune function in the rat. Circulation 90:525–532
Lawlor PA, Young D (2011) A β infusion and related models of alzheimer dementia. In: De Deyn PP, Dam DV (eds) Animal models of dementia, Neuromethods 48. Springer Science and Business Media, Berlin, pp 347–370
Liu RY, Gu R, Qi XL, Zhang T, Zhao Y, He Y, Pei JJ, Guan ZZ (2008) Decreased nicotinic receptors and cognitive deficit in rats intracerebroventricularly injected with beta-amyloid peptide(1-42) and fed a high-cholesterol diet. J Neurosci Res 86:183–193
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275
Mallat M, Chamak B (1994) Brain macrophages: neurotoxic or neurotrophic effector cells? J Leukoc Biol 56:416–422
Maluish AE, Halliday WJ (1979) Hemocytometer leukocyte adherence technique. Cancer Res 39:625–626
Maurice T, Lockhart BP, Privat A (1996) Amnesia induced in mice by centrally administered β-amyloid peptides involves cholinergic dysfunction. Brain Res 706:181–193
McAdams RM, Juul SE (2012) The role of cytokines and inflammatory cells in perinatal brain injury. Neurol Res Int 2012:561494. https://doi.org/10.1155/2012/561494 15 pages
Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T (2000) Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci 20:7116–7121
Nazem A, Sankowski R, Bacher M, Al-Abed Y (2015) Rodent models of neuroinflammation for Alzheimer’s disease. J Neuroinflammation 12:2–15
Nicolle LE, Yoshikawa TT (2000) Urinary tract infection in long-term-care facility residents. Clin Infect Dis 31(3):757–761
Noda M, Nakanishi H, Akaike N (1999) Glutamate release from microglia via glutamate transporter is enhanced by amyloid beta peptide. Neuroscience 92(4):1465–1474
O’Shea SD, Smith IM, McCabe OM, Cronin MM, Walsh DM, O’Connor WT (2008) Intracerebroventricular administration of amyloid β-protein oligomers selectively increases dorsal hippocampal dialysate glutamate levels in the awake rat. Sensors 8:7428–7437
Oben JA, Foreman JC (1988) A simple quantitative fluorimetric assay of in vitro phagocytocis in human neutrophils. J Immunol Methods 112:99–103
Parks JK, Smith TS, Trimmer PA, Bennett JP Jr, Parker WD Jr (2001) Neurotoxic Aβ peptides increase oxidative stress in vivo through NMDA receptor and nitric-oxide synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J Neurochem 76(4):1050–1056
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, San Diego
Popp J, Schaper K, Kolsch H, Cvetanovska G, Rommel F, Klingmuller D, Dodel R, Wullner U, Jessen F (2009) CSF cortisol in Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 30:498–500
Rai S, Kamat PK, Nath C, Shukla R (2013) A study on neuroinflammation and NMDA receptor function in STZ (ICV) induced memory impaired rats. J Neuroimmunol 254:1–9
Sachdeva AK, Chopra K (2015) Lycopene abrogates Aβ(1-42)-mediated neuroinflammatory cascade in an experimental model of Alzheimer’s disease. J Nutr Biochem 26(7):736–744
Selkoe DJ (1996) Amyloid β-protein and the genetics of Alzheimer’s disease. J Biol Chem 271:18295–18298
Shalit F, Sredni B, Stern L, Kott E, Huberman M (1994) Elevated interleukin-6 secretion levels by mononuclear cells of Alzheimer’s patients. Neurosci Lett 174:130–132
Shen WX, Chen JH, Lu JH, Peng YP, Qiu YH (2014) TGF-β1 protection against Aβ 1–42-induced neuroinflammation and neurodegeneration in rats. Int J Mol Sci 15:22092–22108
Sil S, Goswami AR, Dutta G, Ghosh T (2014) Effects of naproxen on some immune responses in colchicine induced rat model of Alzheimer’s disease. Neuroimmunomodulation 21:304–321
Sil S, Ghosh A, Ghosh T (2016) Impairment of blood brain barrier is related with the neuroinflammation induced peripheral immune status in intracerebroventricular colchicine injected rats: an experimental study with mannitol. Brain Res 1646:278–286
Sil S, Ghosh T, Ghosh R, Gupta P (2017) Nitric oxide synthase inhibitor, aminoguanidine reduces intracerebroventricular colchicine induced neurodegeneration, memory impairments and changes of systemic immune responses in rats. J Neuroimmunol 303:51–61
Singh A, Kumar A (2016) Comparative analysis of intrahippocampal amyloid beta (1–42) and it is intracerebroventricular streptozotocin models of Alzheimer’s disease: possible behavioral, biochemical, mitochondrial, cellular and histopathological evidences. J Alzheimers Dis Parkinsonism 6:208. https://doi.org/10.4172/2161-0460.1000208
Sisodia SS, Kim SH, Thinakaran G (1999) Function and dysfunction of the presenilins. AmJHumGenet 65:7–12
Socci DJ, Bjugstad KB, Jones HC, Pattisapu JV, Arendash GW (1999) Evidence that oxidative stress is associated with the pathophysiology of inherited hydrocephalus in the H-Tx rat model. Exp Neurol 155:109–117
Soleret SB, Fioravantla M, Pascale AL, Ferrari E, Govoni S, Battaini F (1998) Increased natural killer cell cytotoxicity in Alzheimer’s disease may involve protein kinase C dysregulation. Neurobiol Aging 19:191–199
Srivareerat M, Tran TT, Salim S, Aleisa AM, Alkadhi KA (2011) Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer’s disease. Neurobiol Aging 32:834–844
Stepanichev MY, Zdobnova IM, Zarubenko II, Moiseeva YV, Lazareva NA, Onufriev MV, Gulyaeva NV (2004) Amyloid-β(25–35)-induced memory impairments correlate with cell loss in rat hippocampus. Physiol Behav 80:647–655
Stepanichev MY, Onufriev MV, Yakovlev AA, Khrenov AI, Peregud DI, Vorontsova ON, Lazareva NA, Gulyaeva NV (2008) Amyloid-beta 25–35 increases activity of neuronal NO-synthase in rat brain. Neurochem Int 52(6):1114–1124
Stevens A, Bancroft JD (eds) (1977) Proteins and nucleic acids. In: Theory and practice of histological techniques. Elsevier, London, p 129
Stuchbury G, Munch G (2005) Alzheimer’s associated inflammation, potential drug targets and future therapies. J Neural Transm 112(3):429–453
Swabb DF, Raadsheer FC, Endert E, Hoffman MA, Kamphorst W, Ravid R (1994) Increased cortisol levels in aging and Alzheimer’s disease in postmortem cerebrospinal fluid. J Neuroendocrinol 6:681–687
Varadarajan S, Yatin S, Aksenova M, Butterfield DA (2000) Review: Alzheimer’s amyloid β-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol 130:184–208
Wada H, Nakajoh K, Satoh-Nakagawa T, Suzuki T, Ohrui T, Arai H, Sasaki H (2001) Risk factors of aspiration pneumonia in Alzheimer’s disease patients. Gerontology 47:271–276
Weidmann E, Brieger J, Jahn B, Hoelzer D, Bergmann L, Mitrou PS (1995) Lactate dehydrogenase release assay: a reliable, nonradioactive technique for analysis of cytotoxic lymphocyte-mediated lytic activity against blasts from acute myelocytic leukemia. Ann Hematol 70:153–158
Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, O’Hare E, Esler WP, Maggio JE, Mantyh PW (1998) Fibrillar 훽-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 18(6):2161–2173
Winbald B, Graf A, Riviere ME, Andreasen N, Ryan JM (2014) Active immunotherapy options for Alzheimer’s disease. Alzheimers Res Ther 6:7
Yamada K, Tanaka T, Han D, Senzaki K, Kameyama T, Nabeshima T (1999) Protective effects of idebenone and α-tocopherol on β-amyloid-(1–42)-induced learning and memory deficits in rats: implication of oxidative stress in β-amyloid-induced neurotoxicity in vivo. Eur J Neurosci 11:83–90
Yatin SM, Varadarajan S, Link CD, Butterfield DA (1999) In vitro and in vivo oxidative stress associated with Alzheimer’s amyloid β-peptide (1–42). Neurobiol Aging 20:325–330
Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vi-tek MP, Hovanesian V (2007) Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease. Neurobiol Aging 28:977–986
Zuliani G, Ranzini M, Guerra G, Rossi L, Munari MR, Zurlo A, Volpato S, Atti AR, Blè A, Fellin R (2007) Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia. J Psychiatr Res 41:686–693
Zussy C, Brureau A, Keller E, Marchal S, Blayo C, Delair B, Ixart G, Maurice T, Givalois L (2013) Alzheimer’s disease related markers, cellular toxicity and behavioral deficits induced six weeks after oligomeric amyloid-β peptide injection in rats. PLoS One 8(1):e53117. https://doi.org/10.1371/journal.pone.0053117
Acknowledgements
Dr. S.N. Kabir (chief scientist, IICB, India), Krishnendu Adhikary (M.Sc student, 2016) and Dr. Debajit Bhowmik (CRNN, University of Calcutta) are acknowledged for their assistance in parts of the work.
Funding
This research work has been funded by the National Tea Research Foundation (NTRF), Tea Board, Kolkata, Govt. of India sponsored research project (Scheme Code No, NTRF: 166/2014).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The recommendations and regulations laid down by the institutional animal ethical committee were strictly followed while performing the experiments.
Conflict of Interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Gupta, P., Sil, S., Ghosh, R. et al. Intracerebroventricular Aβ-Induced Neuroinflammation Alters Peripheral Immune Responses in Rats. J Mol Neurosci 66, 572–586 (2018). https://doi.org/10.1007/s12031-018-1189-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-018-1189-9