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- W3112784650 abstract "Abstract Background This laboratory has demonstrated an important role for the NLRP3 inflammasome in the progression of Alzheimer’s disease (AD) with activation found in post‐mortem tissue from individuals with AD (Heneka et al., 2013) and in transgenic mouse models of AD expressing amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice). However, APP/PS1 mice deficient for NLRP3 were protected from AD‐pathology, with a significant reduction in cleaved‐caspase‐1 and IL‐1β. We wanted to examine the wider implications of NLRP3 inflammasome deficiency beyond IL‐1β, and uncover other pathways and signaling mechanisms employed by microglia to protect the brain from the build up of Aβ. Method RNA sequencing was performed on CD11b + cells from the brains of 4, 6 and 12 month old wildtype, APP/PS1, NLRP3 ‐/‐ and APP/PS1.NLRP3 ‐/‐ mice. Microglia were prepared from the brains of 1‐day old wildtype and NLRP3 ‐/‐ mice for live cell imaging, migratory assays and flow cytometric analysis. In a separate series of experiments CD11b + cells were isolated from the brains of wildtype, APP/PS1, NLRP3 ‐/‐ and APP/PS1.NLRP3 ‐/‐ mice and myeloid cells were also prepared from the blood of humans with and without AD to replicate all findings in these models. Result The RNA sequencing analysis found a significant increase in pathways related to chemokine signaling in NLRP3 ‐/‐ and APP/PS1. NLRP3 ‐/‐ mice. Wildtype microglia significantly migrated to Aβ, however NLRP3 ‐/‐ microglia or cells treated with NLRP3 inhibitors had increased migration to Aβ and greater Aβ phagocytosis, which was associated with CCL2 release and mediated via the receptors CCR2 and CCR4. Importantly, we were able to replicate these findings using monocyte‐derived microglia‐like cells from humans and in NLRP3 ‐/‐ and APP/PS1/NLRP3 ‐/‐ mice ex vivo . Conclusion We have identified a new mechanism where microglia release CCL2 to migrate to Aβ and phagocytose this peptide. Critically, this activity is increased in NLRP3 ‐/‐ cells or those treated with NLRP3‐specific inhibitors, together demonstrating a previously unknown role for the NLRP3 inflammasome in regulating cellular migratory and phagocytic behavior. These findings provide insights into the pathogenesis of AD and importantly highlight the NLRP3 inflammasome as a serious target for prevention and early treatment of AD." @default.
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- W3112784650 date "2020-12-01" @default.
- W3112784650 modified "2023-10-05" @default.
- W3112784650 title "NLRP3 inflammasome activation regulates microglial migration" @default.
- W3112784650 doi "https://doi.org/10.1002/alz.040946" @default.
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