Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.

Background. Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas. Methods. Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1+14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets v ¼ 26 to +6 ppm (step 0.5 ppm). dB 0 maps were acquired separately for a point-by-point dB 0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR) asym ¼ (S [23.5 ppm] 2 S [+3.5 ppm])/S 0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density. Results. The mean APT SI values were 2.1+0.4% in grade II gliomas (n ¼ 8), 3.2+0.9% in grade III gliomas (n ¼ 10), and 4.1+1.0% in grade IV gliomas (n ¼ 18). Significant differences in APT intensity were observed between grades II and III (P , .05) and grades III and IV (P , .05), as well as between grades II and IV (P , .001). There were positive correlations between APT SI and Ki-67 LI (P ¼ .01, R ¼ 0.43) and between APT SI and cell density (P , .05, R ¼ 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P , .001). Conclusions. APT imaging can predict the histopathological grades of adult diffuse gliomas.

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The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE epsilon4.

We report that lysosomotropic agents and cysteine protease inhibitors inhibited protease-resistant prion protein accumulation in scrapie-infected neuroblastoma cells. The inhibition occurred without either apparent effects on normal prion protein biosynthesis or turnover or direct interactions with prion protein molecules. The findings introduce two new classes of inhibitors of the formation of protease-resistant prion protein.The transmissible spongiform encephalopathies (TSEs), or prion diseases, constitute a group of related neurodegenerative disorders characterized by the accumulation in the central nervous system of an abnormal protease-resistant prion protein (PrP-res), which is made posttranslationally from its normal endogenous protease-sensitive isoform, PrP-sen, by an apparent conformational alteration rather than a modification of the covalent structure (for review, see reference 5). The accumulation of PrP-res is a central event in TSE pathogenesis, because it is correlated with infectivity and neurodegeneration (4,19).Recent outbreaks in younger people of new variant Creutzfeldt-Jakob disease (31) and of iatrogenic Creutzfeldt-Jakob disease by cadaveric dura grafting (1) have urged that therapies be developed for TSE diseases. One possible strategy for TSE therapy is to inhibit PrP-res formation in the infected host. Polyanions like sulfated glycans and Congo red inhibit PrP-res formation and scrapie agent replication in scrapieinfected neuroblastoma (ScNB) cells (6,7,9). Tetrapyrrole compounds have been recently identified as potent inhibitors of PrP-res formation in ScNB cells and in a cell-free system (11). Such polyanions and other classes of potential drugs, such as the polyene antibiotics and anthracycline, are also protective against scrapie in rodents when administered near the time of infection. However, these compounds have no therapeutic benefit if administered after the infection has been established (14-16, 18, 20, 29).We have attempted to find a new class of inhibitors of PrP-res accumulation, not only for TSE therapy, but also for elucidating the mechanism of PrP-res accumulation. In this article, we report that lysosomotropic agents and cysteine protease inhibitors inhibit PrP-res accumulation in ScNB cells and, therefore, are new classes of potential anti-TSE drugs.The compounds used in the study were obtained from Sigma, Aldrich, or Peptide Institute, Inc. (Osaka, Japan), and were used as received. The ScNB cultures were grown in minimal essential medium supplemented with 10% fetal bovine serum as described previously (24). Lysosomotropic agents and cysteine protease inhibitors, shown in Table 1, were added at various concentrations to the medium of cells seeded at 5% confluent density, and the cultures were allowed to grow to confluence for 4 days. The cells were then harvested and analyzed for PrP-res content by immunoblotting as described previously (9), except that an enhanced chemifluorescence reagent (JBL Scientific, Inc.) and a Storm PhosphorImager instrument (Molecular Dyna...

Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.

Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.

The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.