Region-specific dendritic simplification induced by Aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes.

BackgroundDendritic simplification, a key feature of the neurodegenerative triad of Alzheimer's disease (AD) in addition to spine changes and neuron loss, occurs in a region-specific manner. However, it is unknown how changes in dendritic complexity are mediated and how they relate to spine changes and neuron loss.ResultsTo investigate the mechanisms of dendritic simplification in an authentic CNS environment we employed an ex vivo model, based on targeted expression of enhanced green fluorescent protein (EGFP)-tagged constructs in organotypic hippocampal slices of mice. Algorithm-based 3D reconstruction of whole neuron morphology in different hippocampal regions was performed on slices from APPSDL-transgenic and control animals. We demonstrate that induction of dendritic simplification requires the combined action of amyloid beta (Aβ) and human tau. Simplification is restricted to principal neurons of the CA1 region, recapitulating the region specificity in AD patients, and occurs at sites of Schaffer collateral input. We report that γ-secretase inhibition and treatment with the NMDA-receptor antagonist, CPP, counteract dendritic simplification. The microtubule-stabilizing drug epothilone D (EpoD) induces simplification in control cultures per se. Similar morphological changes were induced by a phosphoblocking tau construct, which also increases microtubule stability. In fact, low nanomolar concentrations of naturally secreted Aβ decreased phosphorylation at S262 in a cellular model, a site which is known to directly modulate tau-microtubule interactions.ConclusionsThe data provide evidence that dendritic simplification is mechanistically distinct from other neurodegenerative events and involves microtubule stabilization by dendritic tau, which becomes dephosphorylated at certain sites. They imply that treatments leading to an overall decrease of tau phosphorylation might have a negative impact on neuronal connectivity

Special issue on 'Cytoskeletal proteins in health and neurodegenerative disease'

The cytoskeleton is the major intracellular structure that determines the morphology of neurons and maintains their structural integrity. It is therefore not surprising that a disturbance of cytoskeletal structure and functionunderlies many neurodegenerative diseases. This special issue brings together current information on the three majorneuronal cytoskeletal filament systems, microtubules, microfilaments and neurofilaments, and aims to provide a comprehensive overview of the role of the key components of these three systems under both physiological and pathological conditions. It therefore also addresses the role of microtubule-associated proteins (with a focus on tau) and motor proteins (with a focus on kinesin)

Atrial natriuretic peptide in heart failure

AbstractAtrial natriuretic peptide is a peptide hormone of cardiac origin, which is released in response to atrial distension and serves to maintain sodium homeostasis and inhibit activation of the reninangiotensin-aldosterone system. Congestive heart failure is a clinical syndrome characterized by increased cardiac volume and pressure overload with an inability to excrete a sodium load, which is associated with increased activity of systemic neurohumoral and local autocrine and paracrine mechanisms. Circulating atrial natriuretic peptide is greatly increased in congestive heart failure as a result of increased synthesis and release of this hormone. Atrial natriuretic peptide has emerged as an important diagnostic and prognostic serum marker in congestive heart failure. In early heart failure, it may play a key role in preserving the compensated state of asymptomatic left ventricular dysfunction. Despite increased circulating atrial natriuretic peptide in heart failure, the kidney retains sodium and is hyporesponsive to exogenous and endogenous atrial natriuretic peptide. The mechanism for the attenuated renal response is multifactorial and includes renal hypoperfusion, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems. Therapeutic strategies to potentiate the biologic actions of atrial natriuretic peptide may prolong the asymptomatic phase and delay progression to overt congestive heart failure

Evaluation Of Atrial Fibrillation Burden Before Catheter Ablation Predicts Outcome After Pulmonary Vein Isolation

Background: Paroxysmal atrial fibrillation (PAF) is defined as recurrent AF terminating spontaneously within 7 days. This definition allows the consideration of any AF occurrence lasting < 7 days as paroxysmal, irrespective of the frequency and duration of episodes. The aim of this study was to investigate symptomatic AF burden (AFB) defined as total duration of symptomatic AF episodes within 3 months prior to abalation, for prediction of outcome after pulmonary vein isolation (PVI).Methods: A total of 320 consecutive patients with symptomatic AF (PAF=244, men=214, age=58 y) were enrolled. AFB in patients with PAF was defined as time spent in AF within 3 months prior to PVI. After the AFB cut-off point was optimized at 500 h, patients with PAF were categorized into 2 groups: Group 1 - patients with AFB<500 h (n=192), Group 2 - patients with AFB≥500 h (n=52). Patients with persistent AF (PersAF, n = 76) comprised control group (Group 3). PVI was performed either with irrigated tip catheter (n=215) or using cryoballoon (n=105). The endpoint of study was first documented recurrence of AF >30 sec.Results: Symptomatic AFB was found to be appropriate for prediction of outcome after PVI. The freedom from AF within 2 years was observed in 69%, 31%, and 43% patients in Group 1, 2 and 3, respectively (Group 1 vs. Group 2, p <.001; Group 1 vs. Group 3, p< .001; Group 2 vs. Group 3, p = 0.46).Conclusions: Low AFB < 500 h /3 months was associated with better outcome after PVI. Patients with PAF and high AFB should be treated as patients with PersAF

Presence of C-type natriuretic peptide in human kidney and urine

Presence of C-type natriuretic peptide in human kidney and urine. The current study was undertaken to investigate the presence of CNP immunoreactivity in both human kidney and urine. Immunohistochemical staining with an indirect immunoperoxidase method utilizing an antibody which is 100% cross-reactive to both CNP-53 and CNP-22 was performed on five human kidney specimens (three biopsies of normal cadaveric donor kidneys and two of normal autopsy specimens). CNP immunoreactivity was positive in proximal, distal and medullary collecting duct tubular cells in a cytoplasmic and granular staining pattern. CNP immunoreactivity was also determined in the urine of five healthy volunteers utilizing a sensitive and specific double-antibody radioimmunoassay with a mean concentration of 10.8 ± 1.0 pg/ml. With the utilization of high pressure liquid chromatography, this immunoreactivity proved to be consistent with both the low molecular weight form, CNP-22, as well as the high molecular weight form, CNP-53. Urinary excretion of CNP was also measured in normal subjects (N = 5) and in patients with congestive heart failure (CHF, N = 6). CHF patients excreted over three times more CNP than normals (27.2 ± 2.8 vs. 8.7 ± 0.81 pg/min, P < 0.004) despite no difference between the two groups in plasma CNP concentrations (6.97 ± 0.28 vs. 8.08 ± 1.52 pg/ml, P = NS). This study demonstrates for the first time the presence of CNP immunoreactivity in human kidney and suggests that renal tubular cells may be an additional non-vascular site of synthesis for this cardiorenal acting peptide. This study also demonstrates an increase in urinary CNP excretion in congestive heart failure

Laser-sintered thin films of doped SiGe nanoparticles

We present a study of the morphology and the thermoelectric properties of short-pulse laser-sintered (LS) nanoparticle (NP) thin films, consisting of SiGe alloy NPs or composites of Si and Ge NPs. Laser-sintering of spin-coated NP films in vacuum results in a macroporous percolating network with a typical thickness of 300 nm. The Seebeck coefficient is independent of the sintering process and typical for degenerate doping. The electrical conductivity of LS films rises with increasing temperature, best described by a power-law and influenced by two-dimensional percolation effects.Comment: 4 pages, 4 figure

Simulation based draping of dry carbon fibre textiles with cooperating robots

Carbon fibre-reinforced plastic (CFRP) is a promising material for aircraft and other lightweight applications. To be competitive with low-cost metal based solutions highly effective and flexible production technologies are required. For this purpose production systems comprising automated fibre placement or automated tape laying technology are on the market for several years and widely spread. However, there is still a lack of automated systems capable of producing preforms efficiently and flexibly from textile semi-finished goods. Non-crimp fabrics (NCF) and weaves have to undergo considerable shear and reshaping during the layup of 3D-curved preforms in order to properly fit the 2D cut pieces to the moulds. At the Center for Lightweight Production Technology (ZLP) a digital and automated process for the easy draping of large NCF and weave cut pieces with several robots according to the previous draping simulation has been set up and tested in a robotic work cell. The details of converting the draping simulation into correct and easy to setup motions for cooperating robots and how to execute the entire process autonomously, i.e. without teaching the robots, are described. On the basis of preliminary tests the system’s capabilities on a large scale demonstrator part resembling an airplane’s rear pressure bulkhead are evaluated. An overview of the system’s architecture from simulation based planning to detecting, correct gripping, collision free autonomous transport and laydown of the cut pieces is also given