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Conférence mensuelle - Frank Heppner"Immune actions in Alzheimer’s disease”.

Abstract :

Long considered immune-privileged, rich interactions between the brain and the immune system (neuro-immune interactions) have been recently identified and shown to play important roles in physiology and disease. In neurodegenerative diseases, in particular, the impact of the immune system on disease pathogenesis and progression recently has gained major attention.

A major focus of our research is microglia, the brain´s intrinsic macrophages, which play important roles in CNS development, homeostasis and as first responders to pathological events. While it appears that early microglia action in AD has beneficial effects, Aβ-associated chronic activation of microglia resulting in the production of proinflammatory cytokines such as interleukin (IL)-12 and -23 exacerbates AD progression. Inhibiting microglial IL-12 and/or IL-23 either by genetic or pharmacological means in an AD mouse model exhibiting cerebral amyloidosis substantially alleviates AD pathology such as Aβ burden and cognition.

These data underscore the importance of the microglia in AD pathogenesis, and explain why future efforts aimed at tackling AD via utilization of these myeloid cells present an exciting and challenging new research front and offer novel promising therapeutic options.       

Selected publications

Inhibition of IL­12/IL­23 signaling reduces Alzheimer’s disease–like pathology and cognitive decline Johannes vom Berg1,6, Stefan Prokop2,6, Kelly R Miller2, Juliane Obst2, Roland E Kälin2, Ileana Lopategui-Cabezas2,5, Anja Wegner2, Florian Mair1, Carola G Schipke2,3, Oliver Peters3, York Winter4, Burkhard Becher1,7 & Frank L Heppner2,7
Nature Medecine published online 25 November 2012; doi:10.1038/nm.2965

Functional Impairment of Microglia Coincides with Beta- Amyloid Deposition in Mice with Alzheimer-Like Pathology Grietje Krabbe1.¤, Annett Halle2,3., Vitali Matyash1, Jan L. Rinnenthal2, Gina D. Eom2, Ulrike Bernhardt2, Kelly R. Miller2, Stefan Prokop2, Helmut Kettenmann1*", Frank L. Heppner2*" 1 Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany, 2 Department of Neuropathology, Charite ́ -Universita ̈ tsmedizin Berlin, Berlin, Germany, 3 Center of Advanced European Studies and Research (caesar), Bonn, Germany
PLOS ONE April 2013 | Volume 8 | Issue 4 | e60921

Microglia as Dynamic and Essential Components of the Amyloid Hypothesis Sam Gandy1,* and Frank L. Heppner2,* 1Icahn School of Medicine and James J. Peters VA Medical Center, New York, NY 10029, USA 2Department of Neuropathology, Charite ́ – Universita ̈ tsmedizin Berlin, 10117 Berlin, Germany *Correspondence: samuel.gandy@mssm.edu (S.G.), frank.heppner@charite.de (F.L.H.) http://dx.doi.org/10.1016/j.neuron.2013.05.007




Scientific focus :

Research Field 1:

Our group aims to understand the impact of the immune system on the pathogenesis of neurological diseases by generating and utilizing murine disease models. To this effect, we are studying the contribution of specific immune molecules in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD). We are also investigating the detailed mechanism of Abeta-vaccination in AD, namely whether Abeta antibodies exert their action inside or outside the brain.

Research Field 2:

A further line of our research is devoted towards the understanding of the physiological and pathophysiological role of microglia by the use of CD11b-HSVTK mice, which allow for selective ablation of microglia in vivo. Specifically, we investigate how pathogenetic cascades of e.g. AD are altered in the absence of microglia, or how physiological properties such as neurogenetic capabilities are influenced by the lack of microglia in living mice, both on a cellular as well as on a molecular level.

Research Field 3:

The aim of this research field is to dissect the specific chemokine milieu relevant for systemic spread of lymphoma cells – particularly into the CNS - in order to identify novel druggable targets aimed at interfering with lymphoma dissemination as well as utilizing such molecules to transgenetically model the spread of lymphoma cells to the CNS. The scientific background for this line of research is based on the increasing evidence that chemokine signatures specify the organotropism of lymphomas, which is a critical prognostic determinant in the course of disease. Along this line, the migratory pattern of B cell lymphomas to the central nervous system (CNS) has been suggested to be regulated by specific receptor-ligand interactions, which we aim to dissect.