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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 7 th International Symposium on Neuroprotection and Neurorepair was held from May 2 nd to May 5 th, 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 references25

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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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            Prion-Like Behavior and Tau-dependent Cytotoxicity of Pyroglutamylated β-Amyloid

            Extracellular plaques of β-amyloid (Aβ) and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer’s disease (AD). Plaques comprise Aβ fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of AD. Despite the significance of plaques to AD, oligomers are considered to be the principal toxic forms of Aβ 1,2 . Interestingly, many adverse responses to Aβ, such as cytotoxicity 3 , microtubule loss 4 , impaired memory and learning 5 , and neuritic degeneration 6 , are greatly amplified by tau expression. N-terminally truncated, pyroglutamylated (pE) forms of Aβ 7,8 are strongly associated with AD, are more toxic than Aβ1–42 and Aβ1–40, and have been proposed as initiators of AD pathogenesis 9,10 . We now report a mechanism by which pE-Aβ may trigger AD. Aβ3(pE)-42 co-oligomerizes with excess Aβ1–42 to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ1–42 alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ3(pE)-42 plus 95% Aβ1–42 (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ1–42 monomers in the absence of additional Aβ3(pE)-42. LNOs isolated from human AD brain contained Aβ3(pE)-42, and enhanced Aβ3(pE)-42 formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau null background. We conclude that Aβ3(pE)-42 confers tau-dependent neuronal death and causes template-induced misfolding of Aβ1–42 into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ3(pE)-42 acts similarly at a primary step in AD pathogenesis.
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              Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation.

              T cells contribute to the pathophysiology of ischemic stroke by yet unknown mechanisms. Mice with transgenic T-cell receptors (TCRs) and mutations in costimulatory molecules were used to define the minimal immunologic requirements for T cell-mediated ischemic brain damage. Stroke was induced in recombination activating gene 1-deficient (RAG1(-/-)) mice devoid of T and B cells, RAG1(-/-) mice reconstituted with B cells or T cells, TCR-transgenic mice bearing 1 single CD8(+) (2C/RAG2, OTI/RAG1 mice) or CD4(+) (OTII/RAG1, 2D2/RAG1 mice) TCR, mice lacking accessory molecules of TCR stimulation (CD28(-/-), PD1(-/-), B7-H1(-/-) mice), or mice deficient in nonclassical T cells (natural killer T [NKT] and gammadelta T cells) by transient middle cerebral artery occlusion (tMCAO). Stroke outcome was assessed at day 1. RAG1(-/-) mice and RAG1(-/-) mice reconstituted with B cells developed significantly smaller brain infarctions compared with controls, but thrombus formation after FeCl(3)-induced vessel injury was unimpaired. In contrast, TCR-transgenic mice and mice lacking costimulatory TCR signals were fully susceptible to tMCAO similar to mice lacking NKT and gammadelta T cells. These findings were corroborated by adoptive transfer experiments. Our data demonstrate that T cells critically contribute to cerebral ischemia, but their detrimental effect neither depends on antigen recognition nor TCR costimulation or thrombus formation.
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                Author and article information

                Journal
                Exp Transl Stroke Med
                Exp Transl Stroke Med
                Experimental & Translational Stroke Medicine
                BioMed Central
                2040-7378
                2012
                10 August 2012
                : 4
                : 14
                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
                Article
                2040-7378-4-14
                10.1186/2040-7378-4-14
                3431988
                22883324
                d7b4d41c-85e7-47c6-88df-2072036eee33
                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.

                History
                : 31 July 2012
                : 3 August 2012
                Categories
                Meeting Report

                Cardiovascular Medicine
                cerebral ischemia,translational research,small vessel disease,mitochondria,astrogliosis,in vivo imaging,neuroprotection,neurorepair,vascular dementia,alzheimer’s disease

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