Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology

Studies suggest that activation of phosphoinositide 3-kinase-Akt may protect against neuronal cell death in Alzheimer's disease (AD). Here, however, we provide evidence of increased Akt activation, and hyperphosphorylation of critical Akt substrates in AD brain, which link to AD pathogenesis, suggesting that treatments aiming to activate the pathway in AD need to be considered carefully. A different distribution of Akt and phospho-Akt was detected in AD temporal cortex neurons compared with control neurons, with increased levels of active phosphorylated-Akt in particulate fractions, and significant decreases in Akt levels in AD cytosolic fractions, causing increased activation of Akt (phosphorylated-Akt/total Akt ratio) in AD. In concordance, significant increases in the levels of phosphorylation of total Akt substrates, including: GSK3ßSer9, tauSer214, mTORSer2448, and decreased levels of the Akt target, p27kip1, were found in AD temporal cortex compared with controls. A significant loss and altered distribution of the major negative regulator of Akt, PTEN (phosphatase and tensin homologue deleted on chromosome 10), was also detected in AD neurons. Loss of phosphorylated-Akt and PTEN-containing neurons were found in hippocampal CA1 at end stages of AD. Taken together, these results support a potential role for aberrant control of Akt and PTEN signalling in AD.

Disruption of the langerin/CD207 Gene Abolishes Birbeck Granules without a Marked Loss of Langerhans Cell Function

Langerin is a C-type lectin expressed by a subset of dendritic leukocytes, the Langerhans cells (LC). Langerin is a cell surface receptor that induces the formation of an LC-specific organelle, the Birbeck granule (BG). We generated a langerin(-/-) mouse on a C57BL/6 background which did not display any macroscopic aberrant development. In the absence of langerin, LC were detected in normal numbers in the epidermis but the cells lacked BG. LC of langerin(-/-) mice did not present other phenotypic alterations compared to wild-type littermates. Functionally, the langerin(-/-) LC were able to capture antigen, to migrate towards skin draining lymph nodes, and to undergo phenotypic maturation. In addition, langerin(-/-) mice were not impaired in their capacity to process native OVA protein for I-A(b)-restricted presentation to CD4(+) T lymphocytes or for H-2K(b)-restricted cross-presentation to CD8(+) T lymphocytes. langerin(-/-) mice inoculated with mannosylated or skin-tropic microorganisms did not display an altered pathogen susceptibility. Finally, chemical mutagenesis resulted in a similar rate of skin tumor development in langerin(-/-) and wild-type mice. Overall, our data indicate that langerin and BG are dispensable for a number of LC functions. The langerin(-/-) C57BL/6 mouse should be a valuable model for further functional exploration of langerin and the role of BG.

Theory of the near K-edge structure in electron energy loss spectroscopy

Arguments are given that lead to a formalism for calculating near K-edge structure in electron energy loss spectroscopy (EELS). This is essentially a one electron picture, while many body effects may be introduced at different levels, such as the local density approximation to density functional theory or the GW approximation to the electron self-energy. Calculations are made within the all electron LMTO scheme in crystals with complex atomic and electronic structures, and these are compared with experiment. (c) 2004 Elsevier B.V. All rights reserved.

Electron energy-loss near-edge shape as a probe to investigate the stabilization of yttria-stabilized zirconia

The electron energy-loss near-edge structure (ELNES) at the O K edge has been studied in yttria-stabilized zirconia (YSZ). The electronic structure of YSZ for compositions between 3 and 15 mol % Y2O3 has been computed using a pseudopotential-based technique to calculate the local relaxations near the O vacancies. The results showed phase transition from the tetragonal to cubic YSZ at 10 mol % of Y2O3, reproducing experimental observations. Using the relaxed defect geometry, calculation of the ELNES was carried out using the full-potential linear muffin-tin orbital method. The results show very good agreement with the experimental O K-edge signal, demonstrating the power of using ELNES to probe the stabilization mechanism in doped metal oxides.

Effect of relaxation on the oxygen K-edge electron energy-loss near-edge structure in yttria-stabilized zirconia

The electron energy-loss near-edge structure (ELNES) at the oxygen K-edge has been investigated in a range of yttria-stabilized zirconia (YSZ) materials. The electronic structure of the three polymorphs of pure ZrO2 and of the doped YSZ structure close to the 33 mol %Y2O3 composition have been calculated using a full-potential linear muffin-tin orbital method (NFP-LMTO) as well as a pseudopotential based technique. Calculations of the ELNES dipole transition matrix elements in the framework of the NFP-LMTO scheme and inclusion of core hole screening within Slater's transition state theory enable the ELNES to be computed. Good agreement between the experimental and calculated ELNES is obtained for pure monoclinic ZrO2. The agreement is less good with the ideal tetragonal and cubic structures. This is because the inclusion of defects is essential in the calculation of the YSZ ELNES. If the model used contains ordered defects such as vacancies and metal Y planes, agreement between the calculated and experimental O K-edges is significantly improved. The calculations show how the five different O environments of Zr,Y,O, are connected with the features observed in the experimental spectra and demonstrate clearly the power of using ELNES to probe the stabilization mechanism in doped metal oxides.

The near-edge structure in energy-loss spectroscopy: many-electron and magnetic effects in transition metal nitrides and carbides

We investigate the ability of the local density approximation (LDA) in density functional theory to predict the near-edge structure in electron energy-loss spectroscopy in the dipole approximation. We include screening of the core hole within the LDA using Slater's transition state theory. We find that anion K-edge threshold energies are systematically overestimated by 4.22 +/- 0.44 eV in twelve transition metal carbides and nitrides in the rock-salt (B1) structure. When we apply this 'universal' many-electron correction to energy-loss spectra calculated within the transition state approximation to LDA, we find quantitative agreement with experiment to within one or two eV for TiC, TiN and VN. We compare our calculations to a simpler approach using a projected Mulliken density which honours the dipole selection rule, in place of the dipole matrix element itself. We find remarkably close agreement between these two approaches. Finally, we show an anomaly in the near-edge structure in CrN to be due to magnetic structure. In particular, we find that the N K edge in fact probes the magnetic moments and alignments of ther sublattice.