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Boehm-Sturm P.,Max Planck Institute for Neurological Research | Farr T.D.,Max Planck Institute for Neurological Research | Adamczak J.,Max Planck Institute for Neurological Research | Jikeli J.F.,Max Planck Institute for Neurological Research | And 6 more authors.
Contrast Media and Molecular Imaging

During stroke, the reduction of blood flow leads to undersupply of oxygen and nutrients and, finally, to cell death, but also to upregulation of pro-angiogenic molecules and vascular remodeling. However, the temporal profile of vascular changes after stroke is still poorly understood. Here, we optimized steady-state contrast-enhanced magnetic resonance imaging (SSCE MRI) and followed the dynamic changes in vascular architecture for up to 4 weeks after transient middle cerebral artery occlusion (MCAO) in rats. Using MRI diffusion measurements and the changes of transversal relaxation rates ΔR2 and ΔR2*after injection of a superparamagnetic contrast agent, SSCE MRI provided several hemodynamic parameters: relative cerebral blood volume (rCBV), rCBV in small vessels, microvascular density, and relative vessel size. Six rats underwent SSCE MRI before MCAO and at 7, 14, 21 and 28 days after surgery. 5-Bromo-2′deoxyuridine (BrdU) was injected between days 2 and 7 to label proliferating cells during this time. SSCE MRI depicted a decrease in microvessel density and an increase in vessel size in the ischemic striatum after stroke. A persistently decreased MRI vessel density was confirmed with histology at 28 days. BrdU+endothelial cells were found in regions close to the infarct indicating endothelial cell proliferation during the first week after MCAO; however, late-stage angiogenesis, as would be reflected by increased vessel density, was not detected. The optimized SSCE MRI protocol was used to follow spatio-temporal changes of important vessel characteristics, which may contribute to a better understanding of the role of angiogenesis at different stages after stroke. © 2013 John Wiley & Sons, Ltd. Source

Cui H.L.,Baker Heart and Diabetes Institute | Ditiatkovski M.,Baker Heart and Diabetes Institute | Kesani R.,Baker Heart and Diabetes Institute | Bobryshev Y.V.,University of New South Wales | And 5 more authors.
FASEB Journal

Patients with HIV are at an increased risk of cardiovascular disease. In this study we investigated the effect of Nef, a secreted HIV protein responsible for the impairment of cholesterol efflux, on the development of atherosclerosis in two animal models. ApoE-7- mice fed a high-fat diet and C57BL/6 mice fed a high-fat, high-cholesterol diet were injected with recombinant Nef (40 ng/injection) or vehicle, and the effects of Nef on development of atherosclerosis, inflammation, and dyslipidemia were assessed. In apoE -/- mice, Nef significantly increased the size of atherosclerotic lesions and caused vessel remodeling. Nef caused elevation of total cholesterol and triglyceride levels in the plasma while reducing high-density lipoprotein cholesterol levels. These changes were accompanied by a reduction of ABCA1 abundance in the liver, but not in the vessels. In C57BL/6 mice, Nef caused a significant number of lipid-laden macrophages presented in ad-ventitia of the vessels; these cells were absent from the vessels of control mice. Nef caused sharp elevations of plasma triglyceride levels and body weight. Taken together, our findings suggest that Nef causes dyslipidemia and accumulation of cholesterol in macrophages within the vessel wall, supporting the role of Nef in pathogenesis of atherosclerosis in HIV-infected patients. © FASEB. Source

Richter L.,Free University of Berlin | Munter L.-M.,Free University of Berlin | Ness J.,Heinrich Heine University Dusseldorf | Hildebrand P.W.,Charite - Medical University of Berlin | And 9 more authors.
Proceedings of the National Academy of Sciences of the United States of America

Following ectodomain shedding by β-secretase, successive proteolytic cleavages within the transmembrane sequence (TMS) of the amyloid precursor protein (APP) catalyzed by γ-secretase result in the release of amyloid-β (Aβ) peptides of variable length. Aβ peptides with 42 amino acids appear to be the key pathogenic species in Alzheimer's disease, as they are believed to initiate neuronal degeneration. Sulindac sulfide, which is known as a potent γ-secretase modulator (GSM), selectively reduces Aβ42 production in favor of shorter Aβ species, such as Aβ38. By studying APP-TMS dimerization we previously showed that an attenuated interaction similarly decreased Aβ42 levels and concomitantly increased Aβ38 levels. However, the precise molecular mechanism by which GSMs modulate Aβ production is still unclear. In this study, using a reporter gene-based dimerization assay, we found that APP-TMS dimers are destabilized by sulindac sulfide and related Aβ42-lowering compounds in a concentration-dependent manner. By surface plasmon resonance analysis and NMR spectroscopy, we show that sulindac sulfide and novel sulindac-derived compounds directly bind to the Aβ sequence. Strikingly, the attenuated APP-TMS interaction by GSMs correlated strongly with Aβ42-lowering activity and binding strength to the Aβ sequence. Molecular docking analyses suggest that certain GSMs bind to the GxxxG dimerization motif in the APP-TMS. We conclude that these GSMs decrease Aβ42 levels by modulating APP-TMS interactions. This effect specifically emphasizes the importance of the dimeric APP-TMS as a promising drug target in Alzheimer's disease. Source

Wang Y.,German Center for Neurodegenerative Diseases | Mandelkow E.,German Center for Neurodegenerative Diseases | Mandelkow E.,Center for Advanced European Studies and Research | Mandelkow E.,Max Planck Institute for Neurological Research
Biochemical Society Transactions

Tau aggregates are present in several neurodegenerative diseases and correlate with the severity of memory deficit in AD (Alzheimer's disease). However, the triggers of tau aggregation and tau-induced neurodegeneration are still elusive. The impairment of protein-degradation systems might play a role in such processes, as these pathways normally keep tau levels at a low level which may prevent aggregation. Some proteases can process tau and thus contribute to tau aggregation by generating amyloidogenic fragments, but the complete clearance of tau mainly relies on the UPS (ubiquitin-proteasome system) and the ALS (autophagy-lysosome system). In the present paper, we focus on the regulation of the degradation of tau by the UPS and ALS and its relation to tau aggregation. We anticipate that stimulation of these two protein-degradation systems might be a potential therapeutic strategy for AD and other tauopathies. ©The Authors Journal compilation ©2012 Biochemical Society. Source

Hirohashi N.,The University of Shimane | Hirohashi N.,Ochanomizu University | Alvarez L.,Center for Advanced European Studies and Research | Shiba K.,University of Tsukuba | And 11 more authors.
Current Biology

Behavioral traits of sperm are adapted to the reproductive strategy that each species employs. In polyandrous species, spermatozoa often form motile clusters, which might be advantageous for competing with sperm from other males [1]. Despite this presumed advantage for reproductive success [2, 3], little is known about how sperm form such functional assemblies. Previously, we reported that males of the coastal squid Loligo bleekeri produce two morphologically different euspermatozoa that are linked to distinctly different mating behaviors [4]. Consort and sneaker males use two distinct insemination sites, one inside and one outside the female's body, respectively. Here, we show that sperm release a self-attracting molecule that causes only sneaker sperm to swarm. We identified CO2 as the sperm chemoattractant and membrane-bound flagellar carbonic anhydrase as its sensor. Downstream signaling results from the generation of extracellular H+, intracellular acidosis, and recovery from acidosis. These signaling events elicit Ca2+-dependent turning behavior, resulting in chemotactic swarming. These results illuminate the bifurcating evolution of sperm underlying the distinct fertilization strategies of this species. © 2013 Elsevier Ltd. Source

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