Top

Published in:

Open Access 01-12-2015 | Research

Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer’s disease lacking functional B and T cells

Authors: Claudia Späni, Tobias Suter, Rebecca Derungs, Maria Teresa Ferretti, Tobias Welt, Fabian Wirth, Christoph Gericke, Roger M. Nitsch, Luka Kulic

Published in: Acta Neuropathologica Communications | Issue 1/2015

Abstract

Introduction

In Alzheimer’s disease, accumulation and pathological aggregation of amyloid β-peptide is accompanied by the induction of complex immune responses, which have been attributed both beneficial and detrimental properties. Such responses implicate various cell types of the innate and adaptive arm of the immunesystem, both inside the central nervous system, and in the periphery. To investigate the role of the adaptive immune system in brain β-amyloidosis, PSAPP transgenic mice, an established mouse model of Alzheimer’s disease, were crossbred with the recombination activating gene-2 knockout (Rag2 ko) mice lacking functional B and T cells. In a second experimental paradigm, aged PSAPP mice were reconstituted with bone marrow cells from either Rag2 ko or wildtype control mice.

Results

Analyses from both experimental approaches revealed reduced β-amyloid pathology and decreased brain amyloid β-peptide levels in PSAPP mice lacking functional adaptive immune cells. The decrease in brain β-amyloid pathology was associated with enhanced microgliosis and increased phagocytosis of amyloid β-peptide aggregates.

Conclusion

The results of this study demonstrate an impact of the adaptive immunity on cerebral β-amyloid pathology in vivo and suggest an influence on microglia-mediated amyloid β-peptide clearance as a possible underlying mechanism.

Available only for authorised users

Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, et al. Inflammation in neurodegenerative diseases--an update. Immunology. 2014;142:151–66. doi:10.1111/imm.12233.PubMedCentralCrossRefPubMed

Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362:329–44. doi:10.1056/NEJMra0909142.CrossRefPubMed

Selkoe DJ (2011) Alzheimer's disease. Cold Spring Harb Perspect Biol 3: doi:10.1101/cshperspect.a004457.

Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21:383–421.PubMedCentralCrossRefPubMed

Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. doi:10.1016/S1474-4422(15)70016-5.CrossRefPubMed

Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16:358–72. doi:10.1038/nrn3880.CrossRefPubMed

Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006;12:1005–15. doi:10.1038/nm1484.PubMed

Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron. 2009;64:110–22. doi:10.1016/j.neuron.2009.08.039.PubMedCentralCrossRefPubMed

Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer's disease. Nat Immunol. 2015;16:229–36. doi:10.1038/ni.3102.CrossRefPubMed

10.

Du Y, Dodel R, Hampel H, Buerger K, Lin S, Eastwood B, et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology. 2001;57:801–5.CrossRefPubMed

11.

Geylis V, Kourilov V, Meiner Z, Nennesmo I, Bogdanovic N, Steinitz M. Human monoclonal antibodies against amyloid-beta from healthy adults. Neurobiol Aging. 2005;26:597–606. doi:10.1016/j.neurobiolaging.2004.06.008.CrossRefPubMed

12.

Kellner A, Matschke J, Bernreuther C, Moch H, Ferrer I, Glatzel M. Autoantibodies against beta-amyloid are common in Alzheimer's disease and help control plaque burden. Ann Neurol. 2009;65:24–31. doi:10.1002/ana.21475.CrossRefPubMed

13.

Maftei M, Thurm F, Schnack C, Tumani H, Otto M, Elbert T, et al. Increased levels of antigen-bound beta-amyloid autoantibodies in serum and cerebrospinal fluid of Alzheimer's disease patients. PLoS One. 2013;8:e68996. doi:10.1371/journal.pone.0068996.PubMedCentralCrossRefPubMed

14.

Moir RD, Tseitlin KA, Soscia S, Hyman BT, Irizarry MC, Tanzi RE. Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer's disease patients. J Biol Chem. 2005;280:17458–63. doi:10.1074/jbc.M414176200.CrossRefPubMed

15.

Mruthinti S, Buccafusco JJ, Hill WD, Waller JL, Jackson TW, Zamrini EY, et al. Autoimmunity in Alzheimer's disease: increased levels of circulating IgGs binding Abeta and RAGE peptides. Neurobiol Aging. 2004;25:1023–32. doi:10.1016/j.neurobiolaging.2003.11.001.CrossRefPubMed

16.

Qu BX, Gong Y, Moore C, Fu M, German DC, Chang LY, et al. Beta-amyloid auto-antibodies are reduced in Alzheimer’s disease. J Neuroimmunol. 2014;274:168–73. doi:10.1016/j.jneuroim.2014.06.017.PubMedCentralCrossRefPubMed

17.

Weksler ME, Relkin N, Turkenich R, LaRusse S, Zhou L, Szabo P. Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp Gerontol. 2002;37:943–8.CrossRefPubMed

18.

Gold M, Mengel D, Roskam S, Dodel R, Bach JP. Mechanisms of action of naturally occurring antibodies against beta-amyloid on microglia. J Neuroinflammation. 2013;10:5. doi:10.1186/1742-2094-10-5.PubMedCentralCrossRefPubMed

19.

Neff F, Wei X, Nolker C, Bacher M, Du Y, Dodel R. Immunotherapy and naturally occurring autoantibodies in neurodegenerative disorders. Autoimmun Rev. 2008;7:501–7. doi:10.1016/j.autrev.2008.04.010.CrossRefPubMed

20.

Szabo P, Relkin N, Weksler ME. Natural human antibodies to amyloid beta peptide. Autoimmun Rev. 2008;7:415–20. doi:10.1016/j.autrev.2008.03.007.CrossRefPubMed

21.

Britschgi M, Olin CE, Johns HT, Takeda-Uchimura Y, LeMieux MC, Rufibach K, et al. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer’s disease. Proc Natl Acad Sci U S A. 2009;106:12145–50. doi:10.1073/pnas.0904866106.PubMedCentralCrossRefPubMed

22.

Dodel R, Balakrishnan K, Keyvani K, Deuster O, Neff F, Andrei-Selmer LC, et al. Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer’s disease. J Neurosci. 2011;31:5847–54. doi:10.1523/JNEUROSCI.4401-10.2011.CrossRefPubMed

23.

Mengel D, Roskam S, Neff F, Balakrishnan K, Deuster O, Gold M, et al. Naturally occurring autoantibodies interfere with beta-amyloid metabolism and improve cognition in a transgenic mouse model of Alzheimer's disease 24 h after single treatment. Transl Psychiatry. 2013;3:e236. doi:10.1038/tp.2012.151.PubMedCentralCrossRefPubMed

24.

Itagaki S, McGeer PL, Akiyama H. Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer’s disease brain tissue. Neurosci Lett. 1988;91:259–64.CrossRefPubMed

25.

McGeer PL, Akiyama H, Itagaki S, McGeer EG. Immune system response in Alzheimer's disease. Can J Neurol Sci. 1989;16:516–27.PubMed

26.

Parachikova A, Agadjanyan MG, Cribbs DH, Blurton-Jones M, Perreau V, Rogers J, et al. Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiol Aging. 2007;28:1821–33. doi:10.1016/j.neurobiolaging.2006.08.014.PubMedCentralCrossRefPubMed

27.

Pirttila T, Mattinen S, Frey H. The decrease of CD8-positive lymphocytes in Alzheimer's disease. J Neurol Sci. 1992;107:160–5.CrossRefPubMed

28.

Rogers J, Rovigatti U. Immunologic and tissue culture approaches to the neurobiology of aging. Neurobiol Aging. 1988;9:759–62.CrossRefPubMed

29.

Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol. 2002;124:83–92.CrossRefPubMed

30.

Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, et al. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest. 2003;112:415–22. doi:10.1172/JCI18104.PubMedCentralCrossRefPubMed

31.

Richartz-Salzburger E, Batra A, Stransky E, Laske C, Kohler N, Bartels M, et al. Altered lymphocyte distribution in Alzheimer’s disease. J Psychiatr Res. 2007;41:174–8. doi:10.1016/j.jpsychires.2006.01.010.CrossRefPubMed

32.

Jozwik A, Landowski J, Bidzan L, Fulop T, Bryl E, Witkowski JM. Beta-amyloid peptides enhance the proliferative response of activated CD4CD28 lymphocytes from Alzheimer disease patients and from healthy elderly. PLoS One. 2012;7:e33276. doi:10.1371/journal.pone.0033276.PubMedCentralCrossRefPubMed

33.

Lueg G, Gross CC, Lohmann H, Johnen A, Kemmling A, Deppe M, et al. Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease. Neurobiol Aging. 2015;36:81–9. doi:10.1016/j.neurobiolaging.2014.08.008.CrossRefPubMed

34.

Pellicano M, Larbi A, Goldeck D, Colonna-Romano G, Buffa S, Bulati M, et al. Immune profiling of Alzheimer patients. J Neuroimmunol. 2012;242:52–9. doi:10.1016/j.jneuroim.2011.11.005.CrossRefPubMed

35.

Speciale L, Calabrese E, Saresella M, Tinelli C, Mariani C, Sanvito L, et al. Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol Aging. 2007;28:1163–9. doi:10.1016/j.neurobiolaging.2006.05.020.CrossRefPubMed

36.

Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004;13:159–70. doi:10.1093/hmg/ddh019.CrossRefPubMed

37.

Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992;68:855–67.CrossRefPubMed

38.

Jankowsky JL, Melnikova T, Fadale DJ, Xu GM, Slunt HH, Gonzales V, et al. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease. J Neurosci. 2005;25:5217–24. doi:10.1523/JNEUROSCI.5080-04.2005.PubMedCentralCrossRefPubMed

39.

Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother. 2010;1:94–9. doi:10.4103/0976-500X.72351.PubMedCentralCrossRefPubMed

40.

Kulic L, McAfoose J, Welt T, Tackenberg C, Spani C, Wirth F, et al. Early accumulation of intracellular fibrillar oligomers and late congophilic amyloid angiopathy in mice expressing the Osaka intra-Abeta APP mutation. Transl Psychiatry. 2012;2:e183. doi:10.1038/tp.2012.109.PubMedCentralCrossRefPubMed

41.

Paxinos G, Franklin KBJ (2012) The Mouse Brain in Stereotaxic Coordinates (4th Edition). Academic Press, City

42.

Knobloch M, Konietzko U, Krebs DC, Nitsch RM. Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging. 2007;28:1297–306. doi:10.1016/j.neurobiolaging.2006.06.019.CrossRefPubMed

43.

Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 2015;85:519–33. doi:10.1016/j.neuron.2014.11.020.CrossRefPubMed

44.

Simen BB, Duman CH, Simen AA, Duman RS. TNFalpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting. Biol Psychiatry. 2006;59:775–85. doi:10.1016/j.biopsych.2005.10.013.CrossRefPubMed

45.

Tang YP, Wang H, Feng R, Kyin M, Tsien JZ. Differential effects of enrichment on learning and memory function in NR2B transgenic mice. Neuropharmacology. 2001;41:779–90.CrossRefPubMed

46.

Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med. 1998;4:97–100.CrossRefPubMed

47.

Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet. 1999;29:177–85.CrossRefPubMed

48.

Brynskikh A, Warren T, Zhu J, Kipnis J. Adaptive immunity affects learning behavior in mice. Brain Behav Immun. 2008;22:861–9. doi:10.1016/j.bbi.2007.12.008.CrossRefPubMed

49.

Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A. 2004;101:8180–5. doi:10.1073/pnas.0402268101.PubMedCentralCrossRefPubMed

50.

Wolf SA, Steiner B, Akpinarli A, Kammertoens T, Nassenstein C, Braun A, et al. CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J Immunol. 2009;182:3979–84. doi:10.4049/jimmunol.0801218.CrossRefPubMed

51.

Martorana A, Bulati M, Buffa S, Pellicano M, Caruso C, Candore G, et al. Immunosenescence, inflammation and Alzheimer's disease. Longev Healthspan. 2012;1:8. doi:10.1186/2046-2395-1-8.PubMedCentralCrossRefPubMed

52.

Richartz-Salzburger E, Stransky E, Laske C, Kohler N. Premature immunosenescence: a pathogenetic factor in Alzheimer’s disease? Nervenarzt. 2010;81:837–43. doi:10.1007/s00115-009-2918-7.CrossRefPubMed

53.

Zhu Y, Obregon D, Hou H, Giunta B, Ehrhart J, Fernandez F, et al. Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology. J Cell Mol Med. 2011;15:327–38. doi:10.1111/j.1582-4934.2009.00962.x.PubMedCentralCrossRefPubMed

54.

Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging. 1988;9:339–49.CrossRefPubMed

55.

Sohn JH, So JO, Kim H, Nam EJ, Ha HJ, Kim YH, et al. Reduced serum level of antibodies against amyloid beta peptide is associated with aging in Tg2576 mice. Biochem Biophys Res Commun. 2007;361:800–4. doi:10.1016/j.bbrc.2007.07.107.CrossRefPubMed

56.

Monsonego A, Imitola J, Petrovic S, Zota V, Nemirovsky A, Baron R, et al. Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006;103:5048–53. doi:10.1073/pnas.0506209103.PubMedCentralCrossRefPubMed

57.

Town T, Tan J, Flavell RA, Mullan M. T-cells in Alzheimer’s disease. Neuromolecular Med. 2005;7:255–64. doi:10.1385/NMM:7:3:255.CrossRefPubMed

58.

Anderson KM, Olson KE, Estes KA, Flanagan K, Gendelman HE, Mosley RL. Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders. Transl Neurodegener. 2014;3:25. doi:10.1186/2047-9158-3-25.PubMedCentralCrossRefPubMed

59.

Browne TC, McQuillan K, McManus RM, O'Reilly JA, Mills KH, Lynch MA. IFN-gamma Production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer’s disease. J Immunol. 2013;190:2241–51. doi:10.4049/jimmunol.1200947.CrossRefPubMed

60.

Zhang J, Ke KF, Liu Z, Qiu YH, Peng YP. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of abeta1-42-induced Alzheimer’s disease model rats. PLoS One. 2013;8:e75786. doi:10.1371/journal.pone.0075786.PubMedCentralCrossRefPubMed

61.

Fisher Y, Nemirovsky A, Baron R, Monsonego A. T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer’s disease. PLoS One. 2010;5:e10830. doi:10.1371/journal.pone.0010830.PubMedCentralCrossRefPubMed

62.

Fisher Y, Strominger I, Biton S, Nemirovsky A, Baron R, Monsonego A. Th1 polarization of T cells injected into the cerebrospinal fluid induces brain immunosurveillance. J Immunol. 2014;192:92–102. doi:10.4049/jimmunol.1301707.CrossRefPubMed

63.

Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2009;119:182–92. doi:10.1172/JCI36470.PubMedCentralPubMed

64.

Beers DR, Henkel JS, Zhao W, Wang J, Appel SH. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci U S A. 2008;105:15558–63. doi:10.1073/pnas.0807419105.PubMedCentralCrossRefPubMed

65.

Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, et al. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011;134:1293–314. doi:10.1093/brain/awr074.PubMedCentralCrossRefPubMed

66.

Sakaguchi S. Naturally arising Foxp3-expressing CD25 + CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6:345–52. doi:10.1038/ni1178.CrossRefPubMed

67.

Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87. doi:10.1016/j.cell.2008.05.009.CrossRefPubMed

68.

Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4 + CD25 + Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A. 2007;104:19446–51. doi:10.1073/pnas.0706832104.PubMedCentralCrossRefPubMed

69.

Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, et al. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015;6:7967. doi:10.1038/ncomms8967.PubMedCentralCrossRefPubMed

70.

Avidan H, Kipnis J, Butovsky O, Caspi RR, Schwartz M. Vaccination with autoantigen protects against aggregated beta-amyloid and glutamate toxicity by controlling microglia: effect of CD4 + CD25+ T cells. Eur J Immunol. 2004;34:3434–45. doi:10.1002/eji.200424883.CrossRefPubMed

71.

Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol. 2010;184:2261–71. doi:10.4049/jimmunol.0901852.PubMedCentralCrossRefPubMed

72.

Weekman EM, Sudduth TL, Abner EL, Popa GJ, Mendenhall MD, Brothers HM, et al. Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice. J Neuroinflammation. 2014;11:127. doi:10.1186/1742-2094-11-127.PubMedCentralCrossRefPubMed

73.

Wilcock DM. A changing perspective on the role of neuroinflammation in Alzheimer’s disease. Int J Alzheimers Dis. 2012;2012:495243. doi:10.1155/2012/495243.PubMedCentralPubMed

Title: Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer’s disease lacking functional B and T cells
Authors: Claudia Späni
Tobias Suter
Rebecca Derungs
Maria Teresa Ferretti
Tobias Welt
Fabian Wirth
Christoph Gericke
Roger M. Nitsch
Luka Kulic
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-015-0251-x

At a glance: The STEP trials

Springer Medicine

Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer’s disease lacking functional B and T cells

Abstract

Introduction

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2015

IFNβ secreted by microglia mediates clearance of myelin debris in CNS autoimmunity

Erratum to: Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse

microRNA network analysis identifies miR-29 cluster as key regulator of LAMA2 in ependymoma

Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression

PI3 kinase mutations and mutational load as poor prognostic markers in diffuse glioma patients

Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue