期刊
EMBO JOURNAL
卷 38, 期 4, 页码 -出版社
WILEY
DOI: 10.15252/embj.201899430
关键词
Alzheimer's disease; autophagy; BECN1/Beclin1; inflammation; microglia
资金
- Deutsche Forschungsgemeinschaft [SFB TRR 43, SFB TRR 167, NeuroCure Exc 257, HE 3130/6-1]
- Deutsche Forschungsgemeinschaft (DFG) [JE278/6-1]
- Berlin Institute of Health (BIH)
- European Union (PHAGO
- Innovative Medicines Initiative-2)
- Advanced Medical Bioimaging Core Facility (AMBIO) of the Charite-Universitatsmedizin
- DFG [SFB958/Z02]
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.
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