Although the APP increase was rapid but short lived, the BACE1 el

Although the APP increase was rapid but short lived, the BACE1 elevation had a slower onset but was sustained for at least 96 h of Ab42 stimulation. The TNF a IFN g and Ab42 stimulated increases in astrocytic APP and BACE1 were remarkably similar, but some differences were also observed. For example, the APP and BACE1 elevations appeared to involve both transcriptional and post transcriptional mechanisms, but to varying degrees depending on the stimulus. The TNF a IFN g stimulated BACE1 increase was post transcriptional, since BACE1 mRNA levels were reduced, while the Ab42 stimulated BACE1 increase involved BACE1 mRNA elevation. In addition, the early phases of the TNF a IFN g stimulated astrocytic APP elevation did not involve increases in APP mRNA levels, suggesting a post transcriptional mechanism, while the opposite was true for the Ab42 stimulated APP increase.

Potential post transcriptional mechanisms could involve enhanced translation or stability of APP and BACE1 mRNAs or proteins, as previously reported in other sys tems. It remains to be determined whether these mechanisms or others could be responsible for the observed elevations of endogenous APP and BACE1 in astrocytes. To gain insight into the Inhibitors,Modulators,Libraries signaling pathways responsi ble for the TNF a IFN g stimulated increases in astro cytic APP, BACE1 and Ab, we used inhibitors against two signaling molecules known to be involved in neu roinflammation, JAK and iNOS. Except for reducing APP levels with JAK inhibition, blocking neither JAK nor iNOS had a significant effect on astro cytic APP, BACE1, or secreted Ab40 levels.

However, our results do not necessarily mean that these molecules do not play important roles in cytokine stimulated amy loidogenic APP processing in astrocytes, because the JAK and iNOS signaling cascades have complex regula tion and they may adapt to inhibitor treatment. Astrocytic Inhibitors,Modulators,Libraries effect sizes were largest with cytokine combi nations, suggesting that activation of multiple signaling pathways summed together in a synergistic fashion to elevate astrocytic APP, BACE1, and Ab. Further work using multiple inhibitors or genetic knockdown approaches will Inhibitors,Modulators,Libraries be necessary to dissect precisely which signaling molecules are the most critical for Inhibitors,Modulators,Libraries cytokine sti mulated elevations of APP, BACE1, and Ab in astrocytes.

We did not directly address the molecular mechan isms by which Ab42 Inhibitors,Modulators,Libraries raised the levels of APP, selleck compound BACE1, and b secretase processing in astrocytes. However, the higher levels of astrocytic APP and BACE1 mRNA that we observed following Ab42 stimulation suggested increased gene transcription was responsible, at least in part. Little is known about the regulation of APP and BACE1 gene expression in astrocytes. A recent study has suggested that NF B may activate the BACE1 gene promoter in TNF a stimulated astrocytes.

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