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The amyloid beta-protein (Abeta) is the main component of Alzheimer's disease-related senile plaques. Although Abeta is associated with the development of Alzheimer's disease, it has not been shown which forms of Abeta induce neurodegeneration in vivo and which types of neurons are vulnerable. To address these questions, we implanted DiI crystals into the left frontocentral cortex of APP23 transgenic mice overexpressing mutant human APP (amyloid precursor protein gene) and of littermate controls. Traced commissural neurons in layer III of the right frontocentral cortex were quantified in 3-, 5-, 11- and 15-month-old mice. Three different types of commissural neurons were traced. At 3 months of age no differences in the number of labelled commissural neurons were seen in APP23 mice compared with wild-type mice. A selective reduction of the heavily ramified type of neurons was observed in APP23 mice compared with wild-type animals at 5, 11 and 15 months of age, starting when the first Abeta-deposits occurred in the frontocentral cortex at 5 months. The other two types of commissural neurons did not show alterations at 5 and 11 months. At 15 months, the number of traced sparsely ramified pyramidal neurons was reduced in addition to that of the heavily ramified neurons in APP23 mice compared with wild-type mice. At this time Abeta-deposits were seen in the neo- and allocortex as well as in the basal ganglia and the thalamus. In summary, our results show that Abeta induces progressive degeneration of distinct types of commissural neurons. Degeneration of the most vulnerable neurons starts in parallel with the occurrence of the first fibrillar Abeta-deposits in the neocortex, that is, with the detection of aggregated Abeta. The involvement of additional neuronal subpopulations is associated with the expansion of Abeta-deposition into further brain regions. The vulnerability of different types of neurons to Abeta, thereby, is presumably related to the complexity of their dendritic morphology.

PI3Ks control signal transduction triggered by growth factors and G-protein-coupled receptors and regulate an array of biological processes, including cellular proliferation, differentiation, survival and migration. Herein, we investigated the role of PI3Kc in the pathogenesis of EAE. We show that, in the absence of PI3Kc expression, clinical signs of EAE were delayed and mitigated. PI3Kc-deficient myelin oligodendrocyte glycoprotein (MOG) -specific CD4 1 T cells appeared later in the secondary lymphoid organs and in the CNS than their WT counterparts. Transfer of WT CD4 1 cells into PI3Kc À/À mice prior to MOG immunisation restored EAE severity to WT levels, supporting the relevance of PI3Kc expression in Th cells for the pathogenesis of EAE; however, PI3Kc was dispensable for Th1 and Th17 differentiation, thus excluding an altered expression of these pathogenetically relevant cytokines as the cause for ameliorated EAE in PI3Kc À/À mice. These findings demonstrate that PI3Kc contributes to the development of autoimmune CNS inflammation.Keywords: Autoimmune disease . EAE . PI3Kc . T cells Supporting Information available online IntroductionEAE is an autoimmune disorder of the CNS that serves as an animal model for the human disease multiple sclerosis (MS) [1]. Both in MS and EAE, Th1 and Th17 myelin-reactive CD4 1 T lymphocytes gain access to the CNS and, in concert with other infiltrating mononuclear cells such as macrophages, cause inflammation, oligodendrocyte cell death, demyelination, axonal degeneration and progressive ascending paralysis [2][3][4].PI3Kg belongs to the Class IB family of dual-specificity lipid and protein kinases that catalyse the phosphorylation of phosphatidylinositol-4,5-biphosphate into the second messenger phosphatidylinositol-3,4,5-triphosphate [5,6]. First characterised in the early 1990s, PI3Kg is mainly expressed in blood and [28,29]. Yet, the function of PI3Kg in EAE pathogenesis remains unclear. Here, we investigated the effect of PI3Kg deletion on the course of chronic EAE and its influence on the immune mechanisms underlying pathogenesis. ResultsLate onset and reduced severity of EAE in PI3Kc À=À mice Following s.c. immunisation with myelin oligodendrocyte glycoprotein (MOG) peptide in CFA and administration of pertussis toxin i.v., WT mice reproducibly developed a severe, chronic encephalomyelitis with clinical signs of disease appearing between days 13 and 19 post-immunisation (pi) (Fig. 1A). The onset of clinical symptoms in PI3Kg À/À mice was delayed by approximately 10 days compared with the WT mice ( Fig. 1A and Table 1). Disease severity, as judged by the maximal and cumulative clinical scores, was significantly lower in PI3Kg À/À mice (Table 1). Reduced severity was also revealed by the reduced body weight loss that PI3Kg À/À mice experienced during the symptomatic phase of EAE when compared with WT mice (Fig. 1B). Moreover, although more than 90% of the WT mice reached scores Z3, less than 50% of the PI3Kg À/À mice developed a complete hind leg paralysis (score 5 ...

The heat shock genes of Bacillus subtilis are assigned to four classes on the basis of their regulation mechanisms. While classes I and III are negatively controlled by two different transcriptional repressors, class II is regulated by the alternative sigma factor B . All heat shock genes with unidentified regulatory mechanisms, among them htpG, constitute class IV. Here, we show that expression of htpG is under positive control. We identified a DNA sequence (GAAAAGG) located downstream of the A -dependent promoter of htpG. The heat inducibility of the promoter could be destroyed by inversion, nucleotide replacements, or removal of this DNA sequence. Fusion of this sequence to the vegetative lepA promoter conferred heat inducibility. Furthermore, we were able to show that the heat induction factor is dependent on the absolute temperature rather than the temperature increment and that nonnative proteins within the cytoplasm fail to induce htpG.

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