Inflammatory signalling in Alzheimer’s disease

Neuroinflammation is a prominent feature of Alzheimer’s disease (AD) brain that is believed to modulate disease onset and/or progression. Activation of the NLRP3 inflammasome and NFκB-mediated transcription of inflammatory cytokines act in conjunction to cause inflammatory responses in the periphery and central nervous system. The purinoceptor, P2X7R, lies upstream of both NLRP3 and NFκB inflammatory signalling and so represents a key regulator of inflammatory responses.
The aim of this project is to better elucidate the contribution of P2X7R receptor-mediated inflammatory signalling to AD. P2X7R expression will be examined in post-mortem control and AD brain to determine the spatial pattern of P2X7R activation relative to Aβ and pathological tau accumulation, and the association between P2X7R upregulation and local inflammatory responses. A library of P2X7R antagonists will be screened to determine which are the most effective in reducing inflammatory responses in microglia and astrocytes. The most active compounds will be further studied in organotypic brain slice cultures prepared from transgenic models of AD.
The student will acquire cutting-edge cell culture and molecular biology techniques and will use state-of-the-art microscopy equipment available to us in our Nikon Imaging Centre. The student will join a leading AD research team, based in the newly established Maurice Wohl Clinical Neuroscience Institute.

Supervisors: Dr Wendy Noble & Dr Beatriz Perez-Nievas