Alzheimer's disease (AD) is the most common form of dementia and associated with progressive deposition of amyloid b-peptides (Ab) in the brain. Ab derives by sequential proteolytic processing of the amyloid precursor protein by b-and c-secretases. Rare mutations that lead to amino-acid substitutions within or close to the Ab domain promote the formation of neurotoxic Ab assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type Ab and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular Ab undergoes phosphorylation by protein kinases at the cell surface and in cerebrospinal fluid of the human brain. Phosphorylation of serine residue 8 promotes formation of oligomeric Ab assemblies that represent nuclei for fibrillization. Phosphorylated Ab was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated Ab. Phosphorylation of Ab could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD.

Production of neutralizing anti-IL-9 antibodies was induced in mice by immunization with mouse IL-9 coupled to ovalbumin. In the six mouse strains tested, a strong and long-lasting anti-IL-9 response developed with seric inhibitory titers of 10 ؊3 to 10 ؊5 , as measured in an in vitro IL-9-dependent cell proliferation assay. In vivo, this immunization completely abrogated the increase in mast-cell protease-1 levels as well as the eosinophilia observed in mice after implantation of an IL-9-secreting tumor. We took advantage of this method to assess the role of IL-9 in infections with nematode Trichuris muris, where IL-9 production correlates with the resistant phenotype. C57BL͞6 mice, which normally expel the parasite, became susceptible after anti-IL-9 immunization, demonstrating that IL-9 plays a critical role in this model. In addition, neutralization of IL-9 also inhibited parasite-induced blood eosinophilia. Taken together, the present data demonstrate the potency of our strategy to antagonize IL-9 in vivo and shows that this cytokine plays a major role in resistance against T. muris infection.S ince its discovery as a T and mast-cell growth factor produced by Th2 cells (1-3), IL-9 physiological roles have gradually expanded (4). Prominent features, disclosed by analysis of transgenic mice overexpressing IL-9, include increased susceptibility to lymphomagenesis (5), intestinal mastocytosis (6), expansion of the B-1 lymphocyte population (7), bronchial hyperresponsiveness (8, 9), and airway eosinophilia (10). In line with these observations, genetic analyses revealed a linkage between both IL9 and IL9R genes to human asthma (11, 12), a finding that was confirmed, with respect to IL-9, in murine models (13).Although detrimental in asthma, elevated production of Th2 cytokines has been reported to correlate with resistance to certain parasite infections (14). IL-9, for example, was found to enhance mouse resistance to infection with the cecal dwelling nematode Trichuris muris (15). This resistance was associated with high IgE and IgG1 levels, as well as with pronounced intestinal mastocytosis.On the basis of these observations, inhibiting IL-9 activity in vivo would probably be beneficial in asthma and deleterious in parasite infections. To test these predictions and evaluate the actual importance of IL-9 in these processes, we developed a method aimed at inducing anti-IL-9 autoantibodies in vivo.The absence of T cell help has been suggested previously to be crucial for B cell tolerance toward self proteins (16). Therefore, by providing physically linked T cell help, it should be possible to overcome B cell nonresponsiveness toward self antigens. By using bovine luteinizing hormone (LH) as a self protein coupled to ovalbumin (OVA), Johnson et al. (17) were able to induce high titers of autoantibodies against LH, causing cows to become anestrous. Similarly, a vaccine that prevents pregnancy in women was developed by coupling human chorionic gonadotropin and ovine luteinizing hormone to tetanus and diphtheria tox...

Immune responses associated with intestinal nematode infections are characterized by the activation of T-helper 2 (Th2) cells. Previous studies demonstrated that duringTrichinella spiralis infection, Th2 cells contribute to the development of intestinal muscle hypercontractility and to worm eviction from the gut, in part through signal transducer and activator of transcription factor 6 (Stat6). Interleukin-9 (IL-9), a Th2-cellderived cytokine, has pleiotropic activities on various cells that are not mediated through Stat6. In this study, we investigated the role of IL-9 in the generation of enteric muscle hypercontractility in mice infected with the intestinal parasite T. spiralis and the cecal parasite Trichuris muris. Treatment of mice with IL-9 enhanced infection-induced jejunal muscle hypercontractility and accelerated worm expulsion in T. spiralis infection. These effects were associated with an up-regulation of IL-4 and IL-13 production from in vitro-stimulated spleen cells. In addition, increases in the level of intestinal goblet cells and in the level of mouse mucosal mast cell protease 1 (MMCP-1) in serum were observed in infected mice following IL-9 administration. However, the neutralization of IL-9 by anti-IL-9 vaccination or by anti-IL-9 antibody had no significant effect on worm expulsion or muscle contraction in T. spiralis-infected mice. In contrast, the neutralization of IL-9 significantly attenuated T. muris infection-induced colonic muscle hypercontractility and inhibited worm expulsion. The attenuated expulsion of the parasite by IL-9 neutralization was not accompanied by changes in goblet cell hyperplasia or the MMCP-1 level. These findings suggest that IL-9 contributes to intestinal muscle function and to host protective immunity and that its importance and contribution may differ depending on the type of nematode infection.

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During differentiation, neurons require a high lipid supply for membrane formation as they elaborate complex dendritic morphologies. While glia-derived lipids support neuronal growth during development, the importance of cell-autonomous lipid production for dendrite formation has been unclear. Using Drosophila larva dendritic arborization (da) neurons, we show that dendrite expansion relies on cell-autonomous fatty acid production. The nociceptive class four (CIV) da neurons form particularly large space-filling dendrites. We show that dendrite formation in these CIVda neurons additionally requires functional sterol regulatory element binding protein (SREBP), a crucial regulator of fatty acid production. The dendrite simplification in srebp mutant CIVda neurons is accompanied by hypersensitivity of srebp mutant larvae to noxious stimuli. Taken together, our work reveals that cell-autonomous fatty acid production is required for proper dendritic development and establishes the role of SREBP in complex neurons for dendrite elaboration and function.

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BCL3 encodes a protein with close homology to IκB proteins and interacts with p50 NF-κB homodimers. However, the regulation and transcriptional activity of BCL3 remain ill-defined. We observed here that interleukin-9 (IL-9) and IL-4, but not IL-2 or IL-3, transcriptionally upregulated BCL3 expression in T cells and mast cells. BCL3 induction by IL-9 was detected as soon as 4 hours after stimulation and appeared to be dependent on the Jak/STAT pathway. IL-9 stimulation was associated with an increase in p50 homodimers DNA binding activity, which was mimicked by stableBCL3 expression. This contrasts with tumor necrosis factor (TNF)-dependent NF-κB activation, which occurs earlier, involves p65/p50 dimers, and is dependent on IκB degradation. Moreover, IL-9 stimulation or BCL3 transient transfection similarly inhibited NF-κB–mediated transcription in response to TNF. Taken together, our observations show a new regulatory pathway for the NF-κB transcription factors through STAT-dependent upregulation ofBCL3 gene expression.

IL-9 is critically involved in heart transplant eosinophilia in conjunction with IL-4 and IL-5.