| First Author | Terrill-Usery SE | Year | 2014 |
| Journal | Biochim Biophys Acta | Volume | 1842 |
| Issue | 11 | Pages | 2276-85 |
| PubMed ID | 25125050 | Mgi Jnum | J:218466 |
| Mgi Id | MGI:5617650 | Doi | 10.1016/j.bbadis.2014.08.001 |
| Citation | Terrill-Usery SE, et al. (2014) Amyloid-beta(1-42) protofibrils stimulate a quantum of secreted IL-1beta despite significant intracellular IL-1beta accumulation in microglia. Biochim Biophys Acta 1842(11):2276-85 |
| abstractText | Neuroinflammation is a characteristic feature of the Alzheimer's disease (AD) brain. Significant inflammatory markers such as activated microglia and cytokines can be found surrounding the extracellular senile plaques predominantly composed of amyloid-beta protein (Abeta). Several innate immune pathways, including Toll-like receptors (TLRs) and the NLRP3 inflammasome, have been implicated in AD inflammation. Abeta plays a primary role in activating these pathways which likely contributes to the progressive neurodegeneration in AD. In order to better understand the complexities of this interaction we investigated the inflammatory response of primary microglia to Abeta(1-42) protofibrils. Abeta(1-42) protofibrils triggered a time- and MyD88-dependent process that produced tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) mRNA, and intracellular pro and mature forms of IL-1beta protein. The accumulation of both IL-1beta forms indicated that Abeta(1-42) protofibrils were able to prime and activate the NLRP3 inflammasome. Surprisingly, Abeta-induced accumulation of intracellular mature IL-1beta did not translate into greater IL-1beta secretion. Instead, we found that Abeta elicited a quantized burst of secreted IL-1beta and this process occurred even prior to Abeta priming of the microglia suggesting a basal level of either pro or mature IL-1beta in the cultured primary microglia. The IL-1beta secretion burst was rapid but not sustained, yet could be re-evoked with additional Abeta stimulation. The findings from this study demonstrated multiple sites of IL-1beta regulation by Abeta(1-42) protofibrils including TLR/MyD88-mediated priming, NLRP3 inflammasome activation, and modulation of the IL-1beta secretory process. These results underscore the wide-ranging effects of Abeta on the innate immune response. |
