A team at the Hertie Institute for Clinical Brain Research at the University of Tübingen, in cooperation with an international team of scientists, has developed a new transgenic mouse model for Alzheimer’s disease that led to an unexpected result: microglia are not involved in either the formation or the clearance of amyloid plaques.
In a study published in Nature Neuroscience, Stefan Grathwohl and Prof. Mathias Jucker's team (Hertie Institute for Clinical Brain Research, University of Tübingen), in collaboration with Frank Heppner's team (Department of Neuropathology, Charité-Universitätsmedizin Berlin), show how they developed a transgenic mouse model for Alzheimer's disease, in which microglia cells can be almost completely ablated. Such a finding was a necessary prerequisite for the further advance of Alzheimer's research. The scientists analysed what effect the ablation of microglia cells had on amyloid plaques.
Deposits of pathological amyloid-ß proteins, otherwise known as amyloid plaques, can be found in the brains of Alzheimer patients. Since amyloid-ß protein plays a key role in the pathogenesis of Alzheimer's disease, research on the formation and clearance of amyloid-ß protein is crucial for the further understanding of the disease and therefore an important prerequisite for new approaches in the treatment of Alzheimer's disease.
Microglia cells are phagocytes (scavenger cells) that carry out monitoring functions in the brain. It has long been known that microglia cells accumulate in the immediate vicinity of amyloid plaques in the brains of those suffering from Alzheimer's. As a result, it was assumed that microglia cells are involved in the clearance of amyloid deposits.
In collaboration with colleagues from Berlin, the scientists from Tübingen have succeeded in developing a transgenic mouse model in which microglia cells can for the first time be almost completely removed (95%). This was made possible through the introduction of a so-called suicide gene into microglia cells and the administration of a pharmaceutical agent which led to the systematic death of the cells.
Surprisingly and contrary to all predictions, the ablation of microglia had no effect at all on the quantity of amyloid deposits. Whether the microglia cells were eliminated before or after the formation of amyloid-ß protein deposits made no difference. It is known from cell culture experiments that, in principle, microglia cells have the ability to reduce amyloid plaques. Future studies will be put in place to find out why this effect does not occur in the brains of the mouse models. The answer to this question could pave the way for a new therapy for Alzheimer's disease.
Title of publication:Formation and maintenance of β-amyloid plaques in Alzheimer's disease in the absence of microgliaStefan A Grathwohl, Roland E Kälin, Tristan Bolmont, Stefan Prokop, Georg Winkelmann, Stephan A Kaeser, Jörg Odenthal, Rebecca Radde, Therese Eldh, Sam Gandy, Adriano Aguzzi, Matthias Staufenbiel, Paul M Mathews, Hartwig Wolburg, Frank L Heppner, Mathias JuckerNature Neuroscience, in press 2009
University Hospital TübingenCentre for NeurologyHertie Institute for Clinical Brain Research (HIH)Professor Mathias JuckerTel.: +49 (0)7071-29-8 68 63E-mail: mathias.jucker(at)uni-tuebingen.de