Characterisation of PDGF-BB:PDGFRβ signalling pathways in human brain pericytes: evidence of disruption in Alzheimer's disease

Smyth et al. use tissue microarrays from Alzheimer's disease (AD) patient brains to show that PDGF-BB:PDGFR beta signalling components are reduced in AD. They then use primary human brain pericytes to elucidate a pathway by which PDGF-BB:PDGFR beta signalling in brain pericytes is disrupted in AD, thus impairing the blood brain barrier. Platelet-derived growth factor-BB (PDGF-BB):PDGF receptor-beta (PDGFR beta) 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:PDGFR beta signalling components were altered in human AD brains, with a marked reduction in vascular PDGFB. We hypothesised that reduced PDGF-BB:PDGFR beta 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:PDGFR beta signalling through Akt augments pericyte-derived inflammatory secretions. It may therefore be possible to supplement PDGF-BB signalling to stabilise the cerebrovasculature in AD.

Automated summary

Smyth et al. found that PDGF-BB:PDGFR beta signalling components are reduced in AD patient brains, and identified pathways by which PDGF-BB:PDGFR beta signalling in brain pericytes is disrupted in AD. These findings suggest that enhancing PDGF-BB signalling may be a potential therapeutic strategy for improving brain vasculature in AD.