Investigating microglia inflammasome activation and regulation in Alzheimer disease

01 January 2018 → 31 December 2021
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Inflammation
    • Innate immunity
    • Cell death
    • Cell signalling
    • Neurological and neuromuscular diseases
Project description

Microglial cells are the resident mononuclear phagocytes of the central nervous system (CNS) and have a functional role in both immune defense and CNS maintenance. These cells may however also acquire a detrimental pro-inflammatory phenotype that involves the formation of inflammasomes - cytosolic multi-protein complexes responsible for the production of proinflammatory cytokines - and the induction of pyroptosis, a lytic form of cell death that provokes further inflammation. Although activated microglia and the inflammasome have been frequently implicated in many inflammatory disorders, very little is known about their contribution towards neuroinflammation and Alzheimer (AD) pathophysiology. The proposed study aims to fill this gap by focusing on particular components in this pathway. Specifically, we will focus on the caspases -1 and -11 that are activated upon inflammasome assembly, and in turn cleave and activate the classic pro-inflammatory cytokines IL-1b and IL-18 to sustain a neuroinflammatory condition. We
will also investigate the role of A20, a potent brake on the central pro-inflammatory NF-B pathway, in controlling microglial activation, inflammasome assembly, and the downstream proinflammatory effects. Through the use of novel and accurate mouse models, and a variety of in-vivo, in-vitro and ex-vivo techniques, this project will provide an insight into the molecular mechanisms of neuroinflammation and its importance for the pathology of AD.