Characterisation of PDGF-BB:PDGFRβ signalling pathways in human brain pericytes: evidence of disruption in Alzheimer’s disease
Leon Smyth, Blake Highet, Deidre Jansson, Jane Y. Wu, Justin Rustenhoven, Miranda Aalderink, Adelie Y. S. Tan, Susan Li, Rebecca Johnson, Natacha Coppieters, Renée R. Handley, Pritika Narayan, Malvindar K. Singh‐Bains, Patrick Schweder, Clinton Turner, Edward W. Mee, Peter Heppner, Jason Correia, Thomas Park, Maurice A. Curtis, Richard L. M. Faull, Mike Dragunow
Abstract
Platelet-derived growth factor-BB (PDGF-BB):PDGF receptor-β (PDGFRβ) signalling in brain pericytes is critical to the development, maintenance and function of a healthy blood-brain barrier (BBB). Furthermore, BBB impairment and pericyte loss in Alzheimer's disease (AD) is well documented. We found that PDGF-BB:PDGFRβ signalling components were altered in human AD brains, with a marked reduction in vascular PDGFB. We hypothesised that reduced PDGF-BB:PDGFRβ signalling in pericytes may impact on the BBB. We therefore tested the effects of PDGF-BB on primary human brain pericytes in vitro to define pathways related to BBB function. Using pharmacological inhibitors, we dissected distinct aspects of the PDGF-BB response that are controlled by extracellular signal-regulated kinase (ERK) and Akt pathways. PDGF-BB promotes the proliferation of pericytes and protection from apoptosis through ERK signalling. In contrast, PDGF-BB:PDGFRβ signalling through Akt augments pericyte-derived inflammatory secretions. It may therefore be possible to supplement PDGF-BB signalling to stabilise the cerebrovasculature in AD.