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Beclin1-driven Autophagy Modulates the Inflammatory Response of Microglia via NLRP3

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Beclin1-driven Autophagy Modulates the Inflammatory Response of Microglia via NLRP3

Judith Houtman et al. EMBO J.

Abstract

Alzheimer's disease is characterized not only by extracellular amyloid plaques and neurofibrillary tangles, but also by microglia-mediated neuroinflammation. Recently, autophagy has been linked to the regulation of the inflammatory response. Thus, we investigated how an impairment of autophagy mediated by BECN1/Beclin1 reduction, as described in Alzheimer's disease patients, would influence cytokine production of microglia. Acutely stimulated microglia from Becn1 +/- mice exhibited increased expression of IL-1beta and IL-18 compared to wild-type microglia. Becn1 +/- APPPS1 mice also contained enhanced IL-1beta levels. The investigation of the IL-1beta/IL-18 processing pathway showed an elevated number of cells with inflammasomes and increased levels of NLRP3 and cleaved CASP1/Caspase1 in Becn1 +/- microglia. Super-resolation microscopy revealed a very close association of NLRP3 aggregates and LC3-positive vesicles. Interestingly, CALCOCO2 colocalized with NLRP3 and its downregulation increased IL-1beta release. These data support the notion that selective autophagy can impact microglia activation by modulating IL-1beta and IL-18 production via NLRP3 degradation and thus present a mechanism how impaired autophagy could contribute to neuroinflammation in Alzheimer's disease.

Keywords: Alzheimer's disease; BECN1/Beclin1; autophagy; inflammation; microglia.

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