Abstract
Background: PDGFβ receptors and their ligand, PDGF-BB, are upregulated in vivo after neuronal insults such as ischemia. When applied exogenously, PDGF-BB is neuroprotective against excitotoxicity and HIV proteins.
Objective: Given this growth factor's neuroprotective ability, we sought to determine if PDGF-BB would be neuroprotective against amyloid-β (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-β treatment for 24 h decreased surviving cell number in a concentrationdependent manner. Pretreatment with PDGF-BB failed to provide any neuroprotection against amyloid-β in primary neurons and only very limited protective effects in SH-SY5Y cells. In addition to its neuroprotective action, PDGF promotes cell growth and division in several systems, and the application of PDGFBB alone to serum-starved SH-SY5Y cells resulted in an increase in cell number. Amyloid-β attenuated the mitogenic effects of PDGF-BB, inhibited PDGF-BB-induced PDGFβ receptor phosphorylation, and attenuated the ability of PDGF-BB to protect neurons against NMDA-induced excitotoxicity. Despite the ability of amyloid-β to inhibit PDGFβ receptor activation, immunoprecipitation experiments failed to detect a physical interaction between amyloid-β and PDGF-BB or the PDGFβ receptor. However, G protein-coupled receptor transactivation of the PDGFβ receptor (an exclusively intracellular signaling pathway) remained unaffected by the presence of amyloid-β.
Conclusions: As the PDGF system is upregulated upon neuronal damage, the ability of amyloid-β to inhibit this endogenous neuroprotective system should be further investigated in the context of AD pathophysiology.
Keywords: Amyloid-β, PDGF-BB, PDGFβ receptor, growth factor, neuroprotection, Alzheimer disease.
Current Alzheimer Research
Title:Amyloid-β Inhibits PDGFβ Receptor Activation and Prevents PDGF-BBInduced Neuroprotection
Volume: 15 Issue: 7
Author(s): Hui Liu, Golam T. Saffi, Maryam S. Vasefi, Youngjik Choi, Jeff S. Kruk, Nawaz Ahmed, Nyasha Gondora, John Mielke, Zoya Leonenko and Michael A. Beazely*
Affiliation:
- The Departments of Biology, University of Waterloo School of Pharmacy, Kitchener, ON, N2G IC5,Canada
Keywords: Amyloid-β, PDGF-BB, PDGFβ receptor, growth factor, neuroprotection, Alzheimer disease.
Abstract: Background: PDGFβ receptors and their ligand, PDGF-BB, are upregulated in vivo after neuronal insults such as ischemia. When applied exogenously, PDGF-BB is neuroprotective against excitotoxicity and HIV proteins.
Objective: Given this growth factor's neuroprotective ability, we sought to determine if PDGF-BB would be neuroprotective against amyloid-β (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-β treatment for 24 h decreased surviving cell number in a concentrationdependent manner. Pretreatment with PDGF-BB failed to provide any neuroprotection against amyloid-β in primary neurons and only very limited protective effects in SH-SY5Y cells. In addition to its neuroprotective action, PDGF promotes cell growth and division in several systems, and the application of PDGFBB alone to serum-starved SH-SY5Y cells resulted in an increase in cell number. Amyloid-β attenuated the mitogenic effects of PDGF-BB, inhibited PDGF-BB-induced PDGFβ receptor phosphorylation, and attenuated the ability of PDGF-BB to protect neurons against NMDA-induced excitotoxicity. Despite the ability of amyloid-β to inhibit PDGFβ receptor activation, immunoprecipitation experiments failed to detect a physical interaction between amyloid-β and PDGF-BB or the PDGFβ receptor. However, G protein-coupled receptor transactivation of the PDGFβ receptor (an exclusively intracellular signaling pathway) remained unaffected by the presence of amyloid-β.
Conclusions: As the PDGF system is upregulated upon neuronal damage, the ability of amyloid-β to inhibit this endogenous neuroprotective system should be further investigated in the context of AD pathophysiology.
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Cite this article as:
Liu Hui, Saffi T. Golam, Vasefi S. Maryam , Choi Youngjik, Kruk S. Jeff , Ahmed Nawaz , Gondora Nyasha , Mielke John , Leonenko Zoya and Beazely A. Michael*, Amyloid-β Inhibits PDGFβ Receptor Activation and Prevents PDGF-BBInduced Neuroprotection, Current Alzheimer Research 2018; 15 (7) . https://dx.doi.org/10.2174/1567205015666180110110321
DOI https://dx.doi.org/10.2174/1567205015666180110110321 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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