RESEARCH

Degenerative Diseases: Proteins and Inflammation

It is now widely accepted that the immune system plays a significant role in a number of diseases of the central nervous system (CNS), especially in neurodegenerative diseases. The precise mechanisms of how the peripheral or the central immune systems contribute to the development of neurodegenerative diseases remain for the large part unexplained. However, a basic understanding of the pathogenesis is essential for the development of new diagnostic and therapeutic processes, and the following projects have been set up with this in mind:

The role of microglia and lymphocytes in the pathogenesis and immunotherapy of Alzheimer's
Roland Kälin, Li Li, Georg Winkelmann, Nicolas Schröder, Frank Heppner:

The aim of this project is to examine the role of i) microglia, ii) B and T lymphocytes and toll-like receptors in the development of Alzheimer's as well as in immunotherapy. These subprojects are based on the recent development of a transgenic mouse, in which the thymidinkinase of the herpes simplex virus (HSVTK) is under the control of the CD11b-promotor. The administration of Ganciclovor leads to the specific ablation of CD11b-positive cells, through which the in situ cerebral macrophages, microglia, can be deactivated. The crossing of the CD11b-HSVTK mouse with transgenic mouse models of Alzheimer's enables research into the development of the disease in both the presence and the absence of in situ endogenous microglia. We are also studying the role of B and T lymphocytes in the pathogenesis of Alzheimer's by crossing Alzheimer mouse models with mice carrying a defined immune system defect. Furthermore, the molecular mechanisms of immunotherapy are being examined in order to provide a better basis for the development of vaccinations. Within this project, as well as the existing genetically modified mice, a new transgenic mouse model is to be developed and applied.

These projects are funded by the National Institutes of Health (NIH R01 NS046006: Vaccination and microglia in Alzheimer's mouse models) and the DFG within the SFB-TR43 (The brain as a target of inflammatory processes). Collaborators include Prof. M. Jucker, Hertie Institute for Brain Research, Tübingen, und Prof. Burkhard Becher, Experimental Immunology, University of Zürich.

Innate Immunity - Mechanisms of neuroinflammatory and allergic diseases
Nicolas Schröder, Frank Heppner

The focus of this project is to examine the influence of innate immunity on the adaptive immune response in the context of inflammatory diseases. Murine disease models will form the basis for this research, on the one hand an Alzheimer's mouse model, on the other experimental autoimmune encephalitis (EAE). Findings and pathomechanisms from studies carried out simultaneously on allergic diseases such as asthma bronchiale are to be examined on CNS models with the aim of testing similar therapy strategies on analogue pathomechanisms.

The aim is to ascertain the ways in which innate immunity i) influences T-cell response, and ii) induce or modify an immunotolerance. Extra attention will be given to the role of toll-like receptors (TLR) in the activation of antigen presenting cells and mast cells.

These projects are also being funded by the DFG (Schr726/2: Toll-like receptors in the occurrence and inhibition of allergic airway diseases. Collaborative partners are e.g. Prof. M. Maurer, Allergie Centrum - Charité, Prof. R. R: Schumann and Prof. S. Bereswill, Institute of Microbiology, Charité.

Pathogenesis and therapy in inclusion body myositis
Cristiane Blechschmidt, Hans-Hilmar Goebel, Frank Heppner

Idiopathic inflammatory myopathies form the largest group of inherited neuromuscular diseases, which are associated with increased morbidity. In patients over 50, sporadic inclusion body myositis (sIBM) is the most common inflammatory muscle disease. Pathogenesis and aetiology however remain unclear. Histopathologically sIBM is characterised by intrazytoplasmatic inclusion bodies (rimmed vacuoles). According to immunhistochemical studies, the vacuoles contain amyloidogenic proteins such as ß-amyloid, hyperphosphoryliertes tau, ubiquitin and synuklein - all of which are proteins also seen in other neurodegenerative diseases such as Alzheimer's disease. sIBM could therefore also deliver insight into the pathogenesis of other neurodegenerative diseases. Using an established mouse model of sIBM we aim not only to characterise the biochemical composition and origin of inclusion bodies, but also to examine the role of the immune system the pathogenesis of sIBM via specific genetic manipulation.
This project is funded by the Swiss National Funds (SNF Project 320000 - 11607: Modelling inclusion body myositis in mice - a key to dagnostic and therapeutic design).

Selected publications:

Falsig J, Julius C, Margalith I, Schwarz P, Heppner FL, Aguzzi A. A versatile prion replication assay in organotypic brain slices. Nat Neurosci 11(1):109-17 (2008).

N.W.J. Schröder and M. Maurer. The role of innate immunity in asthma: leads and lessons from mouse models. Allergy 62: 579-590 (2007).

Priller J, Prinz M, Heikenwalder M, Zeller N, Schwarz P, Heppner FL, and Aguzzi A. Early and rapid engraftment of bone marrow-derived microglia in scrapie. J. Neurosci 26(45):11753-62 (2006).

Gandy S, Heppner FL. Alzheimer's amyloid immunotherapy: quo vadis? Lancet Neurol 4(8):452-3 (2005).

Buch T, Heppner FL, Tertilt C, Heinen TJAJ, Kremer M, Wunderlich FT, Jung S, Waisman A A. Cre-Inducible Toxin Receptor Mediates Cell Lineage Ablation Following Diphtheria Toxin Administration. Nat Methods 2(6):419-26 (2005).

Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hövelmeyer N, Waisman A, Rülicke T, Prinz M, Priller J, Becher B, Aguzzi. A Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146-152 (2005).

Greter M, Heppner FL, Durell B, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11:328-334 (2005).

Gandy S, and Heppner FL. Breaking Up (Amyloid) is Hard to Do. PLoS Med (12):e417 (2005).

Schröder NWJ and Schumann RR. Single Nucleotide Polymorphisms of Toll-like Receptors and Susceptibilty to Infectious Disease. Lancet Infect Dis 5: 156-164 (2005)

Polymenidou M, Heppner FL*, Pellicioli EC, Urich E, Miele G, Braun N, Wopfner F, Schaetzl H, Becher B, Aguzzi A. Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection. Proc Natl Acad Sci USA 101 Suppl 2:14670-6. (*shared first authorship) (2004).

Gandy S, DeMattos RB, Lemere CA, Heppner FL, Aguzzi A, Ershler WB, Dai J, Fraser P, George Hyslop PSt, Holtzman DM, Walker LC, and Keller E. Non-human primates vaccinated with Alzheimer’s A? develop anti-peptide antibodies and elevated plasma A?: but sera lack obvious tissue amyloid plaque immunoreactivity. Alzheimer Dis Assoc Disord 18(1):44-46 (2004).

Prinz M, Heikenwalder M, Junt T, Schwarz P, Glatzel M, Heppner FL, Fu Y-X, Lipp M, and Aguzzi A. The distance between follicular dendritic cells and nerves controls prion neuroinvasion. Nature 425, 957-962 (2003).

Schröder NWJ, Morath S, Alexander C, Hamann L, Zähringer U, Hartung T, Göbel UB, Weber JR und Schumann RR. Lipoteichoic acid (LTA) of S. pneumoniae and S. aureus activates immune cells via toll-like receptor (TLR)-2, LPS binding protein (LBP) and CD14 while TLR-4 and MD-2 are not involved. J. Biol Chem 278: 15587-15594 (2003).

Heppner FL, Musahl C, Arrighi I, Klein MA, Rülicke T, Oesch B, Zinkernagel RM, Kalinke U, Aguzzi A. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294:178-182 (2001).

Aguzzi A, Glatzel M, Montrasio F, Prinz M, Heppner FL. Interventional strategies against prion diseases. Nat Rev Neurosci 10:745-749 (2001).