| First Author | Houtman J | Year | 2019 |
| Journal | EMBO J | Volume | 38 |
| Issue | 4 | PubMed ID | 30617086 |
| Mgi Jnum | J:278302 | Mgi Id | MGI:6323164 |
| Doi | 10.15252/embj.201899430 | Citation | Houtman J, et al. (2019) Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3. EMBO J 38(4) |
| abstractText | 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. |
