Amyloid-β Inhibits PDGFβ Receptor Activation and Prevents PDGF-BBInduced Neuroprotection

Author(s): Hui Liu, Golam T. Saffi, Maryam S. Vasefi, Youngjik Choi, Jeff S. Kruk, Nawaz Ahmed, Nyasha Gondora, John Mielke, Zoya Leonenko, Michael A. Beazely*.

Journal Name: Current Alzheimer Research

Volume 15 , Issue 7 , 2018

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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.

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Article Details

VOLUME: 15
ISSUE: 7
Year: 2018
Page: [618 - 627]
Pages: 10
DOI: 10.2174/1567205015666180110110321
Price: $58

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