Die Rolle des Immunsystems bei der Alzheimer-Demenz

Zusammenfassung

Die Alzheimer-Demenz (AD) ist eine primär neurodegenerative Erkrankung, die zu einem fortschreitenden Verlust kognitiv-mnestischer Funktionen führt. Im Alzheimergehirn zeigen sich neben einem progredienten Neuronenuntergang neuropathologisch charakteristische Proteinablagerungen in Form sogenannter Alzheimerplaques und intrazellulärer Fibrillenbündel. Bei diesen Prozessen scheint das Immunsystem eine zentrale Rolle zu spielen. In post mortem Alzheimerhirngeweben und im Gehirn von Alzheimermausmodellen tritt eine durch Mikrogliazellen vermittelte Entzündungsreaktion auf. Es gibt Hinweise, dass diese aktivierten “Gehirn-Makrophagen” durch die Sekretion proinflammatorischer Zytokine und zytotoxischer Faktoren den neurodegenerativen Prozess verstärken. Andererseits können Mikrogliazellen durch die Produktion von Wachstumsfaktoren und neuroprotektiven Zytokinen Neurone vor dem Zelluntergang schützen. Insbesondere Mikrogliazellen, die aus dem peripheren Blut in das Gehirn einwandern, scheinen die Aβ-Akkumulation in einem AD-Mausmodell unter- drücken zu können. Die aktuellen Befunde über eine pathologisch relevante Implikation dieser Mikrogliazellen lassen auf die Aufklärung therapierelevanter, auf den Menschen übertragbarer Immunmechanismen hoffen.

Summary

Alzheimer’s disease is a primary neurodegenerative disease, leading to the chronic progredient loss of cognitivemnestic functions. Neuropathological hallmarks of the Alzheimer-brain are a progressive neuronal cell death and the deposition of abnormal proteins in so-called Alzheimerplaques and neurofibrillary tangles. The immune system seems to play a crucial role in these processes. In postmortem Alzheimer brain-tissue and in the brains of Alzheimer mouse models a microglia-mediated inflammatory immune reaction can be observed. There is evidence that activation of these “brain-macrophages” aggravates the neurodegenerative process through their secretion of proinflammatory cytokines and cytotoxic factors. On the other hand microglia can protect neurons from cell death by the production of growth factors and neuroprotective cytokines. In particular, microglia immigrating from the peripheral blood into the brain seem to be capable of suppressing Aβ-accumulation in an AD mouse model. The elucidation of these newly discovered immunomechanisms are of great importance due to their straight conferability to human AD and promising therapeutic implications.

Schlüsselwörter

Alzheimer-Erkrankung - Immunantwort - Mikrogliazellen - antigenpräsentierende Zellen - T-Zellen

Keywords

Alzheimer’s disease - adaptive immune response - microglia - antigen-presenting cells - T-cells

• Literatur

• 1 Aktas O, Ullrich O. et al. Neuronal damage in brain inflammation. Arch Neurol 2007; 64 (02) 185-189.
• 2 Alferink J, Lieberam I. et al. Compartmentalized production of CCL17 in vivo: strong inducibility in peripheral dendritic cells contrasts selective absence from the spleen. J Exp Med 2003; 197 (05) 585-599.
• 3 Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und psychisch gerichtliche Medizin 1907; 64: 146-148.
• 4 Apelt J, Schliebs R. Beta-amyloid-induced glial expression of both proand anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology. Brain Res 2001; 894 (01) 21-30.
• 5 Bickel H. Die Epidemiologie der Demenz. Deutsche Alzheimer Gesellschaft. Informationsblatt1. 2006
• 6 Burbach GJ, Hellweg R. et al. Induction of brainderived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice. J Neurosci 2004; 24 (10) 2421-2430.
• 7 Chen G, Chen KS. et al. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 2000; 408 (6815): 975-979.
• 8 Cyster JG. Chemokines and cell migration in secondary lymphoid organs. Science 1999; 286 (5447): 2098-2102.
• 9 Cron M, Maier W, Zimmer A, Alferink J. Eigene Beobachtungen, nicht veröffentlichte Daten.
• 10 El Khoury J, Toft M. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 2007; 13 (04) 432-438.
• 11 Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 2005; 26 (09) 485-495.
• 12 Ethell DW, Shippy D. et al. A beta-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer’s mice. Neurobiol Dis 2006; 23 (02) 351-361.
• 13 Fischer HG, Bonifas U. et al. Phenotype and functions of brain dendritic cells emerging during chronic infection of mice with Toxoplasma gondii. J Immunol 2000; 164 (09) 4826-4834.
• 14 Frautschy SA, Cole GM. et al. Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid. Am J Pathol 1992; 140 (06) 1389-1399.
• 15 Games D, Adams D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995; 373 (6514) 523-527.
• 16 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297 (5580): 353-356.
• 17 Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992; 256 (5054): 184-185.
• 18 Hendrix S, Nitsch R. The role of T helper cells in neuroprotection and regeneration. J Neuroimmunol 2007; 184 (1–2): 100-112.
• 19 Heneka MT, O’Banion MK. Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 2007; 184 (1–2): 69-91.
• 20 Henkel JS, Engelhardt JI. et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 2004; 55 (02) 221-235.
• 21 Holcomb L, Gordon MN. et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998; 04 (01) 97-100.
• 22 Holcomb L, Gordon MN. et al. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet 1999; 29 (03) 177-185.
• 23 Horuk R, Martin AW. et al. Expression of chemokine receptors by subsets of neurons in the central nervous system. J Immunol 1997; 158 (06) 2882-2890.
• 24 Husemann J, Loike JD. et al. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 2002; 40 (02) 195-205.
• 25 Hyman BT, Marzloff K. et al. The lack of accumulation of senile plaques or amyloid burden in Alzheimer’s disease suggests a dynamic balance between amyloid deposition and resolution. J Neuropathol Exp Neurol 1993; 52 (06) 594-600.
• 26 Iarlori C, Gambi D. et al. Expression and production of two selected beta-chemokines in peripheral blood mononuclear cells from patients with Alzheimer’s disease. Exp Gerontol 2005; 40 (07) 605-611.
• 27 Ishizuka K, Kimura T. et al. Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer`s disease. Psychiatry Clin Neurosci 1997; 51 (03) 135-138.
• 28 Itagaki S, McGeer PL. et al. Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer’s disease brain tissue. Neurosci Lett 1988; 91 (03) 259-264.
• 29 Kostulas N, Li HL. et al. Dendritic cells are present in ischemic brain after permanent middle cerebral artery occlusion in the rat. Stroke 2002; 33 (04) 1129-1134.
• 30 Liu Y, Walter S. et al. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 2005; 128 (Pt 8): 1778-1789.
• 31 Mahnke K, Enk AH. Dendritic cells: key cells for the induction of regulatoryT cells?. Curr Top Microbiol Immunol 2005; 293: 133-150.
• 32 Maurer K, Maurer U. Alzheimer, das Leben eines Arztes und die Karriere einer Krankheit. München: Piper Verlag; 1998
• 33 McGeer PL, Itagaki S. et al. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987; 79 (1–2): 195-200.
• 34 McMenamin PG. Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. J Comp Neurol 1999; 405 (04) 553-562.
• 35 Mennicken F, Maki R. et al. Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends Pharmacol Sci 1999; 20 (02) 73-78.
• 36 Monsonego A, Imitola J. et al. Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid beta-peptide presentation to Th1 cells. J Immunol 2003; 171 (05) 2216-2224.
• 37 Monsonego A, Zota V. et al. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 2003; 112 (03) 415-422.
• 38 Orgogozo JM, Gilman S. et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003; 61 (01) 46-54.
• 39 Park JH, Widi GA. et al. Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer’s transgenic mice. J Neurosci 2006; 26 (51) 13279-13286.
• 40 Priller J, Flugel A. et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 2001; 07 (12) 1356-1361.
• 41 Reichmann G, Schroeter M. et al. Dendritic cells and dendritic-like microglia in focal cortical ischemia of the mouse brain. J Neuroimmunol 2002; 129 (1–2): 125-132.
• 42 Roberson ED, Scearce-Levie K. et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 2007; 316 (5825): 750-754.
• 43 Rogers J, Luber-Narod J. et al. 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; 09 (04) 339-349.
• 44 Schmitt TL, Steger MM. et al. Interactions of the Alzheimer beta amyloid fragment (25–35) with peripheral blood dendritic cells. Mech Ageing Dev 1997; 94 (1–3): 223-232.
• 45 Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science 2002; 298 (5594): 789-791.
• 46 Selkoe DJ, Schenk D. Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 2003; 43: 545-584.
• 47 Serafini B, Rosicarelli B. et al. Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J Neuropathol Exp Neurol 2006; 65 (02) 124-141.
• 48 Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002; 02 (03) 151-161.
• 49 Simard AR, Rivest S. Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer’s disease. Mol Psychiatry 2006; 11 (04) 325-327.
• 50 Simard AR, Soulet D. et al. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 2006; 49 (04) 489-502.
• 51 Sommer B, Sturchler-Pierrat C. et al. Transgenic approaches to model Alzheimer’s disease. Rev Neurosci 2000; 11 (01) 47-51.
• 52 Stalder AK, Ermini F. et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J Neurosci 2005; 25 (48) 11125-11132.
• 53 Sturchler-Pierrat C, Abramowski D. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997; 94 (24) 13287-13292.
• 54 Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol 2005; 17 (01) 1-14.
• 55 Tan J, Abdullah L. et al. CD45 isoform alteration in CD45+ T cells asa potential diagnostic marker of Alzheimer`disease. J Neuroimmunol 132: 164-172.
• 56 Togo T, Akiyama H. et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol 2002; 124 (1–2): 83-92.
• 57 Town T, Tan J. et al. T-cells in Alzheimer’s disease. Neuromolecular Med 2005; 07 (03) 255-264.
• 58 Tzeng SF, Wu JP. Responses of microglia and neural progenitors to mechanical brain injury. Neuroreport 1999; 10 (11) 2287-2292.
• 59 Villeneuve J, Tremblay P. et al. Tumor necrosis factor reduces brain tumor growth by enhancing macrophage recruitment and microcyst formation. Cancer Res 2005; 65 (09) 3928-3936.
• 60 Walker DG, Lue LF. Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer’s disease and other neurodegenerative diseases. J Neurosci Res 2005; 81 (03) 412-425.
• 61 Wegiel J, Imaki H. et al. Cells of monocyte/microglial lineage are involved in both microvessel amyloidosis and fibrillar plaque formation in APPsw tg mice. Brain Res 2004; 1022 (1–2): 19-29.
• 62 Wekerle H. Breaking ignorance: the case of the brain. Curr Top Microbiol Immunol 2006; 305: 25-50.
• 63 Wyss-Coray T. Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer’s. Curr Alzheimer Res 2006; 03 (03) 191-195.
• 64 Yamaguchi H. Illustration of dynamic changes in Alzheimer pathology: from mild cognitive impairment to terminal stage. Neuropathology 2005; 25 (04) 285-287.
• 65 Yuan H, Gaber MW. et al. Radiation-induced permeability and leukocyte adhesion in the rat bloodbrain barrier: modulation with anti-ICAM-1 antibodies. Brain Res 2003; 969 (1–2): 59-69.
• 66 Maier W. et al. Genetik affektiver Störungen. Nervenheilkunde 2007; 26: 876-881.