Innate Immunity as potential therapeutic targets in Alzheimer's disease
All Welcome
Inflammation contributes to the progression of Alzheimer’s disease (AD). On-going research is establishing the NLRP3-inflammasome complex as one of the most important regulators of inflammation in AD. The NLRP3 inflammasome forms a molecular platform inside microglia catalysing the activation of the protease caspase-1. Caspase-1 is responsible for converting the potent pro-inflammatory cytokine interleukin-1β (IL-1β) from an inactive to an active secreted form. Active caspase-1 is present in the brains of humans with AD, suggesting that NLRP3 may contribute to the human condition. NLRP3 is also central to the development of inflammation, pathology and memory deficits in a mouse model of AD. Anti-IL-1 drugs such as the biologicals canakinumab and anakinra do not easily penetrate the brain and there are no molecules known to directly target NLRP3 in clinical use. We found that NSAIDs of the fenamate class were effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume regulated anion channel (VRAC) in macrophages. We characterized several clinically approved and widely used fenamate NSAIDs as NLRP3 inhibitors. Flufenamic acid and mefenamic acid were efficacious in rodents in vivo in NLRP3-dependent models of inflammation in an air pouch and the peritoneum. We also show protective and therapeutic effects of the fenamates using a model of amyloid beta (Aβ)-induced memory loss, and a transgenic mouse model of AD. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors for the treatment of AD. In addition to drug repurposing we are also actively generating novel inhibitors of the NLRP3 inflammasome, and identifying lifestyle factors that contribute to increased NLRP3-dependent inflammation in AD.
Date:
12 July 2016, 13:00 (Tuesday, 12th week, Trinity 2016)
Venue:
NDM Building, Headington OX3 7FZ
Venue Details:
Basement Seminar Room
Speaker:
Dr. David Brough (University of Manchester)
Organising department:
Target Discovery Institute
Organiser:
Andrea Keyte (University of Oxford, Target Discovery Institute)
Organiser contact email address:
andrea.keepence-keyte@ndm.ox.ac.uk
Host:
Dr John Davis (University of Oxford)
Part of:
TDI Seminar Series
Booking required?:
Not required
Audience:
Members of the University only
Editor:
Andrea Keepence-Keyte
