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Severity of arterial defects in the retina correlates with the burden of intracerebral haemorrhage in COL4A1 ‐related stroke
ABSTRACT Mutations in the α1 (COL4A1) or α2 (COL4A2) chains of collagen type IV, a major component of the vascular basement membrane, cause intracerebral haemorrhages with variable expressivity and reduced penetrance by mechanisms that remain poorly understood. Here we sought to investigate the cellular mechanisms of COL4A1‐related intracerebral haemorrhage and identify a marker for haemorrhage risk‐stratification. A combination of histological, immunohistochemical and electron microscopy analyses were used to analyse the brain parenchyma, cerebrovasculature, and retinal vessels of mice expressing the disease‐causi...
Source: The Journal of Pathology - December 20, 2017 Category: Pathology Authors: Julien Ratelade, Nicolas Mezouar, Val érie Domenga‐Denier, Ambre Rochey, Emmanuelle Plaisier, Anne Joutel Tags: Original Paper Source Type: research

Dissociation of nNOS from PSD ‐95 promotes functional recovery after cerebral ischaemia in mice through reducing excessive tonic GABA release from reactive astrocytes
Abstract Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential drug target, the protein‐protein interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 (PSD‐95), is critical to acute ischaemic damage and neurogenesis. We show that nNOS–PSD‐95 dissociation induced by microinjection of a recombinant fusion protein Tat‐nNOS‐N1‐133 or systemic administration of a small molecule ZL006 from days 4 to 10 after photothrombotic ischaemia in mice reduced excessive tonic inhibitio...
Source: The Journal of Pathology - October 20, 2017 Category: Pathology Authors: Yu ‐Hui Lin, Hai‐Ying Liang, Ke Xu, Huan‐Yu Ni, Jian Dong, Hui Xiao, Lei Chang, Hai‐Yin Wu, Fei Li, Dong‐Ya Zhu, Chun‐Xia Luo Tags: Original Paper Source Type: research

HIF ‐1α triggers long‐lasting glutamate excitotoxicity via system xc− in cerebral ischaemia‐reperfusion
Abstract Hypoxia‐inducible factor 1α (HIF‐1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF‐1α might contribute to glutamate‐mediated excitotoxicity during cerebral ischaemia‐reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF‐1α conditional knockout mouse displayed an inhibition in CIR‐induced elevation of extracellular glutamate and N‐methyl‐D‐aspartate receptor (NMDAR) activation. By gene screening for glutamate transporters in corti...
Source: The Journal of Pathology - October 31, 2016 Category: Pathology Authors: Chia ‐Hung Hsieh, Yu‐Jung Lin, Wei‐Ling Chen, Yen‐Chih Huang, Chi‐Wei Chang, Fu‐Chou Cheng, Ren‐Shyan Liu, Woei‐Cherng Shyu Tags: Original Paper Source Type: research

Brain ischaemia induces shedding of a BDNF‐scavenger ectodomain from TrkB receptors by excitotoxicity‐activation of metalloproteinases and γ‐secretases
We report here that both TrkB‐FL and neuronal TrkB‐T1 also undergo ectodomain shedding by metalloproteinases activated after ischemic injury or excitotoxic damage of cortical neurons. Subsequently, the remaining membrane‐bound C‐terminal fragments (CTFs) are cleaved by γ‐secretases within the transmembrane region, releasing their intracellular domains (ICDs) into the cytosol. Therefore, we identify TrkB‐FL and TrkB‐T1 as new substrates of regulated intramembrane proteolysis (RIP), a mechanism that highly contributes to TrkB‐T1 regulation in ischaemia but is minor for TrkB‐FL which is mainly processed by ...
Source: The Journal of Pathology - December 29, 2015 Category: Pathology Authors: Gonzalo S. Tejeda, Sara Ayuso‐Dolado, Raquel Arbeteta, Gema M. Esteban‐Ortega, Oscar G. Vidaurre, Margarita Díaz‐Guerra Tags: Original Paper Source Type: research

Large animal models of atherosclerosis – new tools for persistent problems in cardiovascular medicine
Abstract Coronary heart disease and ischaemic stroke caused by atherosclerosis are leading causes of illness and death worldwide. Small animal models have provided insight into the fundamental mechanisms driving early atherosclerosis, but it is increasingly clear that new strategies and research tools are needed to translate these discoveries into improved prevention and treatment of symptomatic atherosclerosis in humans. Key challenges include better understanding of processes in late atherosclerosis, factors affecting atherosclerosis in the coronary bed, and the development of reliable imaging biomarker tools for risk st...
Source: The Journal of Pathology - October 27, 2015 Category: Pathology Authors: J Shim, RH Al‐Mashhadi, CB Sørensen, JF Bentzon Tags: Special Issue: Models of Human Disease Source Type: research

Large animal models of atherosclerosis – new tools for persistent problems in cardiovascular medicine
Abstract Coronary heart disease and ischemic stroke caused by atherosclerosis are leading causes of illness and death worldwide. Small animal models have provided insight into the fundamental mechanisms driving early atherosclerosis, but it is increasingly clear that new strategies and research tools are needed to translate these discoveries into improved prevention and treatment of symptomatic atherosclerosis in humans. Key challenges include better understanding of processes in late atherosclerosis, factors affecting atherosclerosis in the coronary bed, and the development of reliable imaging biomarker tools for risk str...
Source: The Journal of Pathology - September 28, 2015 Category: Pathology Authors: Shim J, Al‐Mashhadi RH, Sørensen CB, Bentzon JF Tags: Invited Review Source Type: research

Tollip is a critical mediator of cerebral ischaemia–reperfusion injury
Abstract Toll‐like receptor (TLR) signalling plays an important role in regulating cerebral ischaemia–reperfusion (I/R) injury. Toll‐interacting protein (Tollip) is an endogenous negative modulator of TLR signalling that is involved in several inflammatory diseases. Our previous study showed that Tollip inhibits overload‐induced cardiac remodelling. However, the role of Tollip in neurological disease remains unknown. In the present study, we proposed that Tollip might contribute to the progression of stroke and confirmed this hypothesis. We found that Tollip expression was significantly increased in I/R‐challenge...
Source: The Journal of Pathology - June 22, 2015 Category: Pathology Authors: Mingchang Li, Bin Feng, Lang Wang, Sen Guo, Peng Zhang, Jun Gong, Yan Zhang, Ankang Zheng, Hongliang Li Tags: Original Paper Source Type: research

Tollip is a critical mediator of cerebral ischaemia/reperfusion injury
Abstract Toll‐like receptor (TLR) signaling plays an important role in regulating cerebral ischaemia/reperfusion (I/R) injury. Toll‐interacting protein (Tollip) is an endogenous negative modulator of TLR signaling that is involved in several inflammatory diseases. Our previous study showed that Tollip inhibits overload‐induced cardiac remodeling. However, the role of Tollip in neurological disease remains unknown. In the present study, we proposed that Tollip might contribute to the progression of stroke and confirmed this hypothesis. We found that Tollip expression was significantly increased in I/R‐challenged bra...
Source: The Journal of Pathology - May 23, 2015 Category: Pathology Authors: Mingchang Li, Bin Feng, Lang Wang, Sen Guo, Peng Zhang, Jun Gong, Yan Zhang, Ankang Zheng, Hongliang Li Tags: Original Paper Source Type: research