Project The role of interleukin-1 signalling pathway for AD-mediated neuronal hyperactivity

Basic data

Title:
The role of interleukin-1 signalling pathway for AD-mediated neuronal hyperactivity
Duration:
01/11/2014 to 31/10/2016
Abstract / short description:
Accumulation of amyloid plaques, Ca2+ dyshomeostasis and a robust inflammatory response are the key features of Alzheimer’s disease (AD). Our in vivo data (Busche et al., 2008; Brawek et al., 2014), together with data from other groups (Kuchibhotla et al., 2008), has shown that Ca2+ dyshomeostasis of both neurons and microglia is extremely prominent in the vicinity of amyloid plaques. Specifically, plaque vicinity is enriched with hyperactive neurons and microglia exhibiting pathologically increased frequency of spontaneous Ca2+ transients. Here we hypothesize that Ca2+ transients in hyperactive plaque-associated microglia directly trigger activation of NLRP3 inflammasome and caspase-1, thus provoking maturation/release of proinflammatory cytokines (IL-1/IL-18), which, in turn, cause hyperactivity of neurons. To test this hypothesis we will combine several state-of-the-art imaging, pharmacological, and molecular biological techniques with novel approaches for in vivo functional analyses of microglia, which were recently developed in our laboratory. To assess the role of activation of NLRP3 inflammasome in microglia and subsequent microglial release of IL-1/IL-18 for AD-related neuronal dysfunction we will (i) characterize intracellular Ca2+ levels and activity patterns of neurons in NLRP3 and caspase-1 knockout mice; (ii) assess in vivo Ca2+ signaling of plaque-associated microglia in conditions of knock-out/blockade of the IL-1 signaling pathway and (iii) understand the consequence of NSAIDs treatment/pharmacological blockade of the IL-1 signaling pathway for AD-associated Ca2+ dyshomeostasis and neuronal network dysfunction. The results obtained will significantly advance our understanding of the mechanisms underlying neuronal network dysfunction in amyloid-depositing brain and will decipher the specific role of IL-1/IL-18 release from microglia. Should our hypothesis turn true, our data will lay the groundwork for new therapeutic strategies for treatment of AD patients.

Involved staff

Managers

Institute of Physiology
Non-clinical institutes, Faculty of Medicine

Contact persons

Institute of Physiology
Non-clinical institutes, Faculty of Medicine
Institute of Physiology
Non-clinical institutes, Faculty of Medicine

Local organizational units

Physiology II
Institute of Physiology
Non-clinical institutes, Faculty of Medicine

Funders

Düsseldorf, Nordrhein-Westfalen, Germany
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