3D NMR structure of a complex between the amyloid beta peptide (1–40) and the polyphenol ε-viniferin glucoside: Implications in Alzheimer's disease

Background

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. There is a consensus that Aβ is a pathologic agent and that its toxic effects, which are at present incompletely understood, may occur through several potential mechanisms. Polyphenols are known to have wide-ranging properties with regard to health and for helping to prevent various diseases like neurodegenerative disorders. Thus inhibiting the formation of toxic Aβ assemblies is a reasonable hypothesis to prevent and perhaps treat AD

Methods

Solution NMR and molecular modeling were used to obtain more information about the interaction between the Aβ_1–40 and the polyphenol ε-viniferin glucoside (EVG) and particularly the Aβ residues involved in the complex.

Results

The study demonstrates the formation of a complex between two EVG molecules and Aβ_1–40 in peptide characteristic regions that could be in agreement with the inhibition of aggregation. Indeed, in previous studies, we reported that EVG strongly inhibited in vitro the fibril formation of the full length peptides Aβ_1–40 and Aβ_1–42, and had a strong protective effect against PC12 cell death induced by these peptides.

Conclusion

For the full length peptide Aβ_1–40, the binding sites observed could explain the EVG inhibitory effect on fibrillization and thus prevent amyloidogenic neurotoxicity.

General significance

Even though this interaction might be important at the biological level to explain the protective effect of polyphenols in neurodegenerative diseases, caution is required when extrapolating this in vitro model to human physiology.     

Ezrin-Radixin-Moesin-binding Phosphoprotein 50 (EBP50) and Nuclear Factor-κB (NF-κB): A FEED-FORWARD LOOP FOR SYSTEMIC AND VASCULAR INFLAMMATION*

The interaction between vascular cells and macrophages is critical during vascular remodeling. Here we report that the scaffolding protein, ezrin-binding phosphoprotein 50 (EBP50), is a central regulator of macrophage and vascular smooth muscle cells (VSMC) function. EBP50 is up-regulated in intimal VSMC following endoluminal injury and promotes neointima formation. However, the mechanisms underlying these effects are not fully understood. Because of the fundamental role that inflammation plays in vascular diseases, we hypothesized that EBP50 mediates macrophage activation and the response of vessels to inflammation. Indeed, EBP50 expression increased in primary macrophages and VSMC, and in the aorta of mice, upon treatment with LPS or TNFα. This increase was nuclear factor-κB (NF-κB)-dependent. Conversely, activation of NF-κB was impaired in EBP50-null VSMC and macrophages. We found that inflammatory stimuli promote the formation of an EBP50-PKCζ complex at the cell membrane that induces NF-κB signaling. Macrophage activation and vascular inflammation after acute LPS treatment were reduced in EBP50-null cells and mice as compared with WT. Furthermore, macrophage recruitment to vascular lesions was significantly reduced in EBP50 knock-out mice. Thus, EBP50 and NF-κB participate in a feed-forward loop leading to increased macrophage activation and enhanced response of vascular cells to inflammation.     

Lateral organization of biological membranes

The lateral organization of biological membranes is of great importance in many biological processes, both for the formation of specific structures such as super-complexes and for function as observed in signal transduction systems. Over the last years, AFM studies, particularly of bacterial photosynthetic membranes, have revealed that certain proteins are able to segregate into functional domains with a specific organization. Furthermore, the extended non-random nature of the organization has been suggested to be important for the energy and redox transport properties of these specialized membranes. In the work reported here, using a coarse-grained Monte Carlo approach, we have investigated the nature of interaction potentials able to drive the formation and segregation of specialized membrane domains from the rest of the membrane and furthermore how the internal organization of the segregated domains can be modulated by the interaction potentials. These simulations show that long-range interactions are necessary to allow formation of membrane domains of realistic structure. We suggest that such possibly non-specific interactions may be of great importance in the lateral organization of biological membranes in general and in photosynthetic systems in particular. Finally, we consider the possible molecular origins of such interactions and suggest a fundamental role for lipid-mediated interactions in driving the formation of specialized photosynthetic membrane domains. We call these lipid-mediated interactions a ‘lipophobic effect.’     

Diatoms, silicic acid and biogenic silica dynamics along the salinity gradient of the Scheldt estuary (Belgium/The Netherlands)

The Scheldt estuary (Belgium/The Netherlands) was sampled along the entire salinity gradient from 2003 to 2005 for silicic acid (DSi), biogenic silica (BSi), suspended particulate matter (SPM) and pigments. Net DSi consumption and/or release within the estuary were investigated by comparing measured DSi concentrations with (fully-transient) model simulations of the concentrations that would have been obtained in case of conservative transport. The DSi consumption was at maximum in May due to diatoms of presumably marine origin blooming in the lower estuary. DSi consumption decreased rapidly in July, probably because of the grazing pressure of copepods also of marine origin, and DSi was released from late summer onwards. Multiple regression analyses showed that most of the BSi did not follow the dynamics of the living diatoms but rather that of the SPM. They also suggested that diatoms were more silicified in the upper estuary than in the lower estuary. Phytoliths were not expected to contribute significantly to the BSi pool. As BSi dynamics strongly differed from those of diatoms and DSi, this study highlighted the importance of taking BSi into account when investigating estuarine silica dynamics. This study also revealed the fundamental role of the coupling between the biogeochemical and ecological functioning of the lower estuary and that of the adjacent coastal zone. This contrasts with the classical consideration that estuaries act as one-way filters for dissolved and particulate material of riverine origin.     

Putative involvement of Thioredoxin h in early response to gravitropic stimulation of poplar stems

Gravity perception and gravitropic response are essential for plant development. In herbaceous species, it is widely accepted that one of the primary events in gravity perception involves the displacement of amyloplasts within specialized cells. However, the early signaling events leading to stem reorientation are not fully known, especially in woody species in which primary and secondary growth occur. Thirty-six percent of the identified proteins that were differentially expressed after gravistimulation were established as potential Thioredoxin targets. In addition, Thioredoxin h expression was induced following gravistimulation. In situ immunolocalization indicated that Thioredoxin h protein co-localized with the amyloplasts located in the endodermal cells. These investigations suggest the involvement of Thioredoxin h in the first events of signal transduction in inclined poplar stems, leading to reaction wood formation.     

On a Minimal Model for Hemodynamics and Metabolism of Lactate: Application to Low Grade Glioma and Therapeutic Strategies

WHO II low grade glioma evolves inevitably to anaplastic transformation. Magnetic resonance imaging is a good non-invasive way to watch it, by hemodynamic and metabolic modifications, thanks to multinuclear spectroscopy ¹H/³¹P. In this work we study a multi-scale minimal model of hemodynamics and metabolism applied to the study of gliomas. This mathematical analysis leads us to a fast-slow system. The control of the position of the stationary point brings to the concept of domain of viability. Starting from this system, the equations bring to light the parameters that push glioma cells out of their domain of viability. Four fundamental factors are highlighted. The first two are cerebral blood flow and the rate of lactate transport through monocarboxylate transporters, which must be reduced in order to push glioma out of its domain of viability. Another factor is the intra arterial lactate, which must be increased. The last factor is pH, indeed a decrease of intra cellular pH could interfere with glioma growth. These reflections suggest that these four parameters could lead to new therapeutic strategies for the management of low grade gliomas.