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Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain – current trends in basic, translational and clinical research

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      Abstract

      The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood–brain barrier, recent findings regarding the pathomechanism of Alzheimer’s disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting.

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      Most cited references 31

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      Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders.

      The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.
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        Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.

        Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
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          Central nervous system pericytes in health and disease.

          Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier (BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.
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            Author and article information

            Affiliations
            [1 ]Fraunhofer-Institute for Cell Therapy and Immunology, Perlickstr. 1, D-04103 Leipzig, Germany
            [2 ]Translational Centre for Regenerative Medicine, University of Leipzig, Philipp-Rosenthal-Str. 55, D-04103 Leipzig, Germany
            [3 ]Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, D-97080 Würzburg, Germany
            [4 ]Leibniz Institute for Neurobiology, Project Group Neuropharmacology, Brenneckestr. 6, D-39118 Magdeburg, Germany
            [5 ]German Centre for Neurodegenerative Diseases (DZNE), site Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
            [6 ]Institute of Neurobiochemistry, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
            [7 ]Department of Neurology, University of Leipzig, Liebigstr. 20, D-04103, Leipzig Germany
            Contributors
            Journal
            Exp Transl Stroke Med
            Exp Transl Stroke Med
            Experimental & Translational Stroke Medicine
            BioMed Central
            2040-7378
            2012
            10 August 2012
            : 4
            : 14
            3431988
            2040-7378-4-14
            22883324
            10.1186/2040-7378-4-14
            Copyright ©2012 Boltze et al.; licensee BioMed Central Ltd.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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            Meeting Report

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