Amyloid-β inhibits PDGFβ receptor activation and prevents PDGF-BB-induced neuroprotection.

Background: PDGF beta receptors and their ligand, PDGF-BB, are upregulated in vivo after neu-ronal insults such as ischemia. When applied exogenously, PDGF-BB is neuroprotective against excito-toxicity and HIV proteins. Objective: Given this growth factor's neuroprotective ability, we sought to determine if PDGF-BB would be neuroprotective against amyloid-beta (1-42), one of the pathological agents associated with Alzheimer's disease (AD). Methods and Results: In both primary hippocampal neurons and the human-derived neuroblastoma cell line, SH-SY5Y, amyloid-beta treatment for 24 h decreased surviving cell number in a concentration-dependent manner. Pretreatment with PDGF-BB failed to provide any neuroprotection against amyloid-beta in primary neurons and only very limited protective effects m SH-SY5Y cells. In addition to its neuropro-tective action, PDGF promotes cell growth and division in several systems, and the application of PDGF-BB alone to serum-starved SH-SY5Y cells resulted in an increase in cell number. Amyloid-beta attenuated the mitogenic effects of PDGF-BB, inhibited PDGF-BB-induced PDGF beta receptor phosphorylation, and attenuated the ability of PDGF-BB to protect neurons against NMDA-induced excitotoxicity. Despite the ability of amyloid-beta to inhibit PDGF beta receptor activation, Immunoprecipitation experiments failed to detect a physical interaction between amyloid-beta and PDGF-BB or the PDGF beta receptor. However, G protein-coupled receptor transactivation of the PDGF beta receptor (an exclusively intracellular signaling pathway) remained unaffected by the presence of amyloid-beta. Conclusions: As the PDGF system is upregulated upon neuronal damage, the ability of amyloid-beta to inhibit this endogenous neuroprotective system should be further investigated m the context of AD pathophysiology.