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Mary neurons from these mice showed enhanced sensitivity to glutamateinduced excitotoxicity. These results in PS1M146V/M146V mice were confirmed independently in PrP promoterdriven transgenic mice expressing the L286V variant [31]. At a mechanistic level, it has been reported that reported that PS1M146V/M146V mice exhibit disrupted intracellular Ca2+ signaling in neurons [33], suggesting that neurons expressing mutant PS1 variants have a lower threshold for excitotoxicity-mediated degenerationVeeraraghavalu et al. Molecular Neurodegeneration 2013, 8:41 http://www.molecularneurodegeneration.com/content/8/1/Page 7 of(reviewed in 1-Oleoyl lysophosphatidic acid [34]). In this regard, we have demonstrated enhanced vulnerability of excitatory neurons in layer 2 (ECL2) of the entorhinal cortex in transgenic mice expressing the FAD-linked PS1E9 variant following perforant pathway (PP) transection, compared with PPlesioned transgenic mice expressing wild-type human PS1 [35]. Finally, we report that CM of microglia from PS1M146V/+ mice inhibits PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/11836127 proliferation of AHNPCs derived from PS1+/+mice. These findings support our earlier observations using CM of microglia from mice expressing PrP-driven PSEN1 transgenes [12]. The identity of the factors in mutant microglia CM and signaling pathways that are responsible for suppression of AHNPC proliferation are not fully understood. However, we showed earlier that eotaxin (or CCL11), Cxcl16, leptin and TIMP-1 (Tissue Inhibitor of Metalloprotease) are factors that were consistently elevated in the CM from microglia expressing FAD-linked PS1E9 and PS1M146L variants [12]. In this regard, Wyss-Coray and colleagues [36] have offered a tantalizing insight. It is well-established that the proliferation and differentiation of AHNPC declines precipitously as a function of age [10], and Villeda et al. [36], sought to identify bloodborne factors in the systemic milieu that inhibit or promote adult neurogenesis in an age-dependent fashion in mice. One factor that was significantly elevated in the plasma of old mice was CCL11 that binds to, and activates the CCR3 chemokine receptor that is expressed by AHNPCs [37]. The nature of signaling pathways in AHNPCs that are activated upon binding of CCL11 or other factors secreted by microglia remain to be determined, and are areas of active investigation.(m ?SEM). Two-way ANOVA test (SPSS ver. 12), were performed for comparisons of quantitative data while analyzing data from multiple groups on AHNPC proliferation or differentiation studies. Tuckey or LSD test were used as a post-hoc analysis. T-test (Unpaired) was performed while comparing data from two independent data sets. Values of p < 0.05 were used as the criterion for statistical significance. Animal experiments were conducted in accordance with institutional and National Institutes of Health guidelines.EE setting and BrdU injectionsFor exposure to EE, cohorts of mentioned 1 month old male transgenic, wild type or PS1 M146V KI (heterozygous or homozygous) animals were housed in large cages containing running wheels, tunnels, toys, and chewable materials for 3 h a day for 1 month. Control groups of animals were maintained in standard laboratory housing conditions. Mice received a single i.p. injection of BrdU (100 mg/kg, Sigma, St. Louis, MO) on the last day of the enrichment. Half of the mice in each group were sacrificed 1 day after the injection to determine progenitor proliferation as described earlier [12]. For AHNPC differentiation studies, mice.