title: Amyloid-β(1-42) protofibrils stimulate a quantum of secreted IL-1β despite significant intracellular IL-1β accumulation in microglia.
abstract: 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-β protein (Aβ). Several innate immune pathways, including Toll-like receptors (TLRs) and the NLRP3 inflammasome, have been implicated in AD inflammation. Aβ 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 Aβ(1-42) protofibrils. Aβ(1-42) protofibrils triggered a time- and MyD88-dependent process that produced tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1β) mRNA, and intracellular pro and mature forms of IL-1β protein. The accumulation of both IL-1β forms indicated that Aβ(1-42) protofibrils were able to prime and activate the NLRP3 inflammasome. Surprisingly, Aβ-induced accumulation of intracellular mature IL-1β did not translate into greater IL-1β secretion. Instead, we found that Aβ elicited a quantized burst of secreted IL-1β and this process occurred even prior to Aβ priming of the microglia suggesting a basal level of either pro or mature IL-1β in the cultured primary microglia. The IL-1β secretion burst was rapid but not sustained, yet could be re-evoked with additional Aβ stimulation. The findings from this study demonstrated multiple sites of IL-1β regulation by Aβ(1-42) protofibrils including TLR/MyD88-mediated priming, NLRP3 inflammasome activation, and modulation of the IL-1β secretory process. These results underscore the wide-ranging effects of Aβ on the innate immune response.
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience University of Missouri-St. Louis, St. Louis, MO, USA.
authors.forename: Shana E
authors.initials: SE
authors.lastname: Terrill-Usery
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience University of Missouri-St. Louis, St. Louis, MO, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mohan
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience University of Missouri-St. Louis, St. Louis, MO, USA. Electronic address: nicholsmic@umsl.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Nichols
keywords: Amyloid-beta protein; Interleukin 1-beta; Microglia; NLRP3 inflammasome; Protofibril; Toll-like receptors