Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3

EMBO J. 2019 Feb 15;38(4):e99430. doi: 10.15252/embj.201899430. Epub 2019 Jan 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / immunology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / physiology
  • Animals
  • Autophagosomes
  • Autophagy*
  • Beclin-1 / physiology*
  • Cytokines / metabolism
  • Female
  • Inflammasomes
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Microglia / immunology*
  • Microglia / metabolism
  • Microglia / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Plaque, Amyloid / immunology*
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Presenilin-1 / physiology


  • Amyloid beta-Protein Precursor
  • Beclin-1
  • Becn1 protein, mouse
  • Cytokines
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Presenilin-1