What have we learned from mouse models of CAA

These mouse models of CAA allowed us to rigorously study the mechanism and impact of CAA. We have subsequently shown that CAA leads to cerebral hemorrhage and that CAA is the cause of the increased cerebral hemorrhage after passive Ap immunization (Fig. 2; Pfeifer et al. 2002), an observation that is now considered a potential serious complication of Ap-immunotherapy in humans. By crossing APP Dutch transgenic mice with several other transgenic mouse models, we found that a high ratio of soluble Ap40/Ap42 drives amyloid formation in the vasculature, whereas a low Ap40/Ap42

Fig. 2. Amyloid pathology in the neocortex of a control (a) and an age-matched immunized APP23 mouse (b). Hemosiderin staining reveals an increased number of microhemorrhages (arrowheads) in the immunized (d) compared to control mice (c). (Reproduced with permission from Pfeifer et al. 2002)

ratio leads to parenchymal amyloid. We have further shown that neuronally derived Ap is transported extracellularly over considerable distances to the vasculature to be cleared via transport into the blood or via perivascular fluid drainage pathway (Meyer-Luehmann et al. 2003; Herzig et al. 2004). Although these and many other findings have begun to highlight the importance of CAA in AD, much more research is necessary to understand its pathogenesis and clinical impact.

Acknowledgements. I want to thank Donald Ingram and Matthias Staufenbiel for their great support. It was the enthusiasm of Donald Ingram that shaped my interest in brain aging, and it was the support of Matthias Staufenbiel that helped me to step into the field of Alzheimer's disease. Over all these years, Konrad Beyreuther greatly supported my work. I also want to thank the many talented students and postdocs in my laboratory for their tremendous contributions and the late-night discoveries.

Jean-François Foncin

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