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There is increasing evidence that ischemic stroke aggravates dementia resulting in a “snowball” effect. In the case of cerebral amyloid angiopathy (CAA) patients do not only establish dementia but also microbleeds, lobar hermorrhages and ischemic stroke. We hypothesize that the intimate interactions between amyloid deposition, inflammatory response, blood-brain-barrier (BBB) disturbances and ischemia contribute to ongoing neurodegeneration. We will study the influence of ischemic stroke on amyloid pathology and vice versa by evaluating the key players of the neurovascular unit, e.g. BBB.

Hereby in-vitro models and amyloid transgenic mouse models will be employed and analyzed by imaging techniques for neuronal networks, reorganization and BBB transporter functions following induction of ischemic stroke. Through a multidisciplinary cross-disease analysis combining pharmacologic biotechnologists, radiopharmacologists, BBB-, imaging-, biomarker- and Alzheimer experts and stroke expertise we will offer a novel perception of neurodegeneration. This will be undertaken by exploiting the

excellent ongoing collaboration between partners of an FP7 project funded by the European Union.

Research questions that will be addressed are 1) Are BBB changes a consequence of Aß deposition in the cerebral vasculature? 2) Does perfusion, neuronal network changes or vascular Aß deposition occur before the development of cerebral amyloid plaques? 3) Will existing amyloid deposition alter pathophysiological reaction to stroke? 4) Will ischemia influences amyloid deposition in the long-term? 5) Are there biomarkers identifying BBB disturbances or amyloid transportation proteins? 6) Could these biomarkers be used in the clinical situation?

The project will focus on dynamic shifts in endothelial ABC transporter patterns using CAA models that are exposed to transient MCAO. Tight junction expression levels as well as mediators of Aß endocytosiswill be correlated to relevant signaling pathways like oxidative stress, hypoxia and inflammation.

Advanced imaging techniques will be applied. Moreover, we propose to identify new biomarkers and molecular pathways through the use of the TgCRND8 and APP23 APP-transgenic mice line as an experimental model of cerebral ß-amyloidosis and will verify these findings in a clinical multi-center study of CAA patients with stroke using MRI, PET and CSF analysis in the acute and chronic phase.

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