Min Jian, Hong Kong PRC
The University of Hong Kong MedicineAuthor Of 1 Presentation
CIRCULATORY ADIPONECTIN INHIBITS IL1BETA SECRETION FROM MICROGLIA THROUGH NLRP3-INFLAMMASOME PATHWAY IN ALZHEIMER’S DISEASE MOUSE MODEL
Abstract
Aims
Adiponectin (APN) is a circulatory adipokine, which possesses anti-inflammatory effects. APN does not expressed in the brain, but low-molecular-weight APN includes trimeric and hexameric forms crosses the blood-brain barrier. We have reported that APN level was reduced in human AD brains and AD mice. Microglia expresses adiponectin receptors and is activated under chronic APN deficiency. However, the molecular implication of APN in microglia-mediated neuroinflammation has not been elucidated.
Methods
APN-deficient 5xFAD mice were generated by crossing APN-/- and 5xFAD mice. Microglia was isolated and RNA was extracted for RNA sequencing. AAV2/8 serotype carrying APN gene with C39S mutation under hAAT/APOE promoter, which allowed liver specific expression of APNTri. 5xFAD mice were given with liver-specific AAV-APNTri (1 x 1011 viral particles) by intravenous injection. Brains were collected for immunofluorescent staining, ELISA and western blot analysis to investigate the role of APN in microglia.
Results
APN modulates neuroinflammatory pathways as shown by RNA sequencing analysis. We have found that APN deficiency increases NLRP3 activation in 5xFAD mice. Microglia activation and IL1β levels are exacerbated under APN-deficiency. In addition, liver-specific expression of APNTri by AAV delivery increases the circulatory APN levels and improves memory functions in AD mice. AAV-APNTri treatment reduces microglia activation and IL1b levels in the brain of 5xFAD in which NLRP3, ASC and caspase-1 levels are also reduced in microglia.
Conclusions
Taken altogether, our study demonstrates the circulatory APN inhibits IL1β secretion from microglia through NLRP3 inhibition, suggesting that increasing periphery trimeric APN can be a potential AD therapy.