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Curr Alzheimer Res. 2018;15(7):618-627. doi: 10.2174/1567205015666180110110321.

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

Author information

1
The Departments of Biology, University of Waterloo School of Pharmacy, Kitchener, ON, N2G IC5, Canada.
2
Faculty of Science, and the School of Public Health and Health Systems, Faculty of Applied Health Science, University of Waterloo School of Pharmacy, Kitchener, ON, N2G IC5, Canada.
3
Physics and Astronomy, University of Waterloo School of Pharmacy, Kitchener, ON, N2G IC5, Canada.

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:

Alzheimer disease; Amyloid-β; PDGF-BB; PDGFβ receptor; growth factor; neuroprotection.

[Indexed for MEDLINE]

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