In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein.In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.
The exact sites, structures, and molecular mechanisms of interaction between junction organizing zona occludence protein 1 (ZO-1) and the tight junction protein occludin or the adherens junction protein ␣-catenin are unknown. Binding studies by surface plasmon resonance spectroscopy and peptide mapping combined with comparative modeling utilizing crystal structures led for the first time to a molecular model revealing the binding of both occludin and ␣-catenin to the same binding site in ZO-1. Our data support a concept that ZO-1 successively associates with ␣-catenin at the adherens junction and occludin at the tight junction. Strong spatial evidence indicates that the occludin C-terminal coiled-coil domain dimerizes and interacts finally as a four-helix bundle with the identified structural motifs in ZO-1. The helix bundle of occludin 406 -521 and ␣-catenin Different junctional complexes such as adherens junctions and, in specialized tissues, tight junctions, gap junctions, and desmosomes connect cells in multicellular organisms. TJ 1 seal the most apical-lateral parts of cells and constitute a diffusion barrier for the paracellular flow of molecules and serve as a fence between the apical and basolateral membrane compartment (1). In contrast, AJ play important roles in cell adhesion, migration, morphogenesis, and proliferation. AJ represent Ca 2ϩ -dependent cell-cell contacts localized basolateral of TJ, where transmembrane proteins of the cadherin family mediate adhesion. Assembly of AJ is a prerequisite for the formation of TJ and desmosomes (2). -and ␣-catenin bind to the cadherin cytoplasmic domain and link the cadherin-catenin complex to the F-actin cytoskeleton. An important scaffolding protein in cell-cell contacts is the zona occludens protein 1. ZO-1 is a membrane associated guanylate kinase homologue protein composed of the following domains: three PDZ (PSD95/Dlg/ZO-1), a SH3, a GuK (3), an actin binding region (4), and a ZU5 (ZO-1 and Unc5-like netrin receptor domain) according SMART (Simple Modular Architecture Research Tool (smart.embl-heidelberg.de) data base (5)). In non-epithelial cells ZO-1 is a major component of AJ, whereas in epithelial cells it is localized at TJ by directly binding to claudins (6). Occludin, one of the transmembrane proteins of TJ, is a multiphosphoprotein involved in regulation of TJ (7). It has four transmembrane domains with two extracellular loops and a cytosolic N and C terminus. A sequence of 244 amino acids in human ZO-1 containing the GuK domain and an acidic region C terminus to GuK binds to the complete intracellular C-terminal tail of chicken occludin (8).ZO-1 also binds to the AJ protein ␣-catenin (9) and to connexins in gap junctions (10), indicating a general scaffolding function of ZO-1 in junctional complexes. ␣-Catenin consists of several four-helix-bundle domains (vinculin homology domains, VH1-3) and binds -catenin via an intermolecular helix bundle mechanisms within the E-cadherin-catenin complex at the intracellular side of AJ, where one helix of ...
Primary angiitis of the central nervous system (PACNS) represents a rare inflammatory disease affecting the brain and spinal cord. Stroke, encephalopathy, headache and seizures are major clinical manifestations. The diagnosis of PACNS is based on the combination of clinical presentation, imaging findings (magnetic resonance imaging and angiography), brain biopsy, and laboratory and cerebral spinal fluid (CSF) values. PACNS can either be confirmed by magnetic resonance angiography (MRA)/conventional angiography or tissue biopsy showing the presence of typical histopathological patterns. Identification of PACNS mimics is often challenging in clinical practice, but crucial to avoid far-reaching treatment decisions. In view of the severity of the disease, with considerable morbidity and mortality, early recognition and treatment initiation is necessary. Due to the rareness and heterogeneity of the disease, there is a lack of randomized data on treatment strategies. Retrospective studies suggest the combined administration of cyclophosphamide and glucocorticoids as induction therapy. Immunosuppressants such as azathioprine, methotrexate or mycophenolate mofetil are often applied for maintenance therapy. In addition, the beneficial effects of two biological agents (anti-CD20 monoclonal antibody rituximab and tumour necrosis factor-α blocker) have been reported. Nevertheless, diagnosis and treatment is still a clinical challenge, and further insights into the immunopathogenesis of PACNS are required to improve the diagnosis and management of patients. The present review provides a comprehensive overview of diagnostics, differential diagnoses, and therapeutic approaches of adult PACNS.
The interaction between tight junction proteins occludin and zona occludens protein 1 (ZO-1) was clarified. The sequence cc1 within the hinge region of ZO-1, connecting its SH3 and GuK domains, was identified as a new association site for the occludin C-terminus, core binding area GLRSSKRNLRKSR (mouse ZO-1(606-618)). Occludin also bound to the sequence H2 within GuK, core area HKLRKNNH (ZO-1(759-766)). In occludin, the binding core was ELSRLDKELDDYREESEEY (mouse occludin(455-473)). Helicity of the sequences was suggested by circular dichroism. Because basic residues in ZO-1, acidic residues in occludin (underlined), coiled-coil helix-forming leucine heptad motifs (bold) in occludin and, probably, in cc1 were essential, we conclude that interactions were both helical and ionic. Moreover, the GuK domain bound other GuK molecules, suggesting oligomerization of ZO-1. Generally, the assumption is supported that the SH3-hinge-GuK region represents a functional and regulatory unit in ZO-1 forming a multiprotein tight junction complex with occludin.
Neutrophil granulocytes (or polymorphonuclear cells, PMNs) have long been considered as crude killing machines, particularly trained to attack bacterial or fungal pathogens in wounds or infected tissues. That perspective has fundamentally changed over the last decades, as PMNs have been shown to exert a livery exchange between other cells of the innate and adaptive immune system. PMNs do provide major immunomodulatory contribution during acute inflammation and subsequent clearance. Following sterile inflammation like cerebral ischemia, PMNs are among the first hematogenous cells attracted to the ischemic tissue. As inflammation is a crucial component within stroke pathophysiology, several studies regarding the role of PMNs following cerebral ischemia have been carried out. And indeed, recent research suggests a direct connection between PMNs' influx and brain damage severity. This review highlights the latest research regarding the close interconnection between PMNs and co-working cells following cerebral ischemia. We describe how PMNs are attracted to the site of injury and their tasks within the inflamed brain tissue and the periphery. We further report of new findings regarding the interaction of PMNs with resident microglia, immigrating macrophages and T cells after stroke. Finally, we discuss recent research results from experimental studies in the context with current clinical trials and point out potential new therapeutic applications that could emerge from this new knowledge on the action and interaction of PMNs following cerebral ischemia.
Background and Purpose-Sleep-related breathing disorders occur frequently after stroke. We assessed the feasibility of continuous positive airway pressure (CPAP) treatment initiated in the first night after stroke. Methods-In this open-label, parallel-group trial, 50 patients were randomly assigned to the CPAP therapy or to the control group. All patients underwent polysomnography in the fourth night. Intervention patients received CPAP therapy for 3 nights starting the first night after stroke onset and for an additional 4 nights when polysomnography revealed an apnea-hypopnea index Ͼ10/hour. The primary end point was feasibility defined as apnea-hypopnea index reduction under CPAP treatment, nursing workload, and CPAP adherence.
Background and Purpose-Although several studies have shown beneficial effects of training in animal stroke models, the most effective training strategy and the optimal time to initiate training have not been identified. The present metaanalysis was performed to compare the efficacy of different training strategies and to determine the optimal time window for training in animal stroke models. Methods-We searched the literature for studies analyzing the efficacy of training in animal models of ischemic stroke.Training was categorized into forced physical training, voluntary physical training, constraint-induced movement therapy, and skilled reaching training. Two reviewers independently extracted data on study quality, infarct size, and neurological outcome. Data were pooled by means of a meta-analysis. Results-Thirty-five studies with >880 animals were included. A meta-analysis of all treatments showed that training reduced the infarct volume by 14% (95% confidence interval, 2%-25%) and improved the cognitive function by 33% (95% confidence interval, 8%-50%), the neuroscore by 13.4% (95% confidence interval, 1.5%-25.3%), and the running function by 6.6% (95% confidence interval, 1.4%-11.9%). Forced physical training reduced the infarct volume and enhanced the running function most effectively, whereas skilled reaching training improved the limb function most effectively. A meta-regression illustrated that training was particularly efficacious when initiated between 1 and 5 days after stroke onset. Conclusions-Our meta-analysis confirms that training reduces the infarct volume and improves the functional recovery in animal stroke models. Forced physical training and skilled reaching training were identified as particularly effective training strategies. The efficacy of training is time dependent. (Stroke. 2014;45:239-247.)
p53 family proteins carry on a wide spectrum of biological functions from differentiation, cell cycle arrest, apoptosis and chemosensitivity of tumors. Conversely, N-terminally truncated p73 (DNp73) functions as a potent inhibitor of all these tumor suppressor properties, implicating its participation in malignant transformation and oncogenesis. Several reports indicated considerable up-regulation of DNp73 in hepatocellular carcinoma (HCC) that correlates with reduced survival of patients, but little is known about the functional significance of DNp73 to tumorigenesis in vivo due to the lack of an appropriate model. To address this, we generated transgenic mice in which DNp73 expression is directed to the liver by the albumin promoter. Gene expression was tested by mRNA and protein analyses. Transgenic mice exhibited prominent hepatic histological abnormalities including increased hepatocyte proliferation resulting in preneoplastic lesions (liver cell adenomas) at 3-4 months. Among 12- to 20-month-old mice, 83% of animals developed hepatic carcinoma. HCC displayed a significant increase of hyperphosphorylated inactive retinoblastoma, whereas p53-regulated inhibitors of cell cycle progression were down-regulated in the tumors. Our data firmly establish the unique oncogenic capability of DNp73 to drive hepatocarcinogenesis in vivo, supporting its significance as a marker for disease severity in patients and as target for cancer prevention. This model offers new opportunities to further delineate DNp73-mediated liver oncogenesis but may also enable the development of more effective cancer therapies.
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