α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP


Roberts, H. L., Schneider, B. L. and Brown, D., 2017. α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP. PLoS ONE, 12 (2), e0171925.

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a-Synuclein misfolding and aggregation is often accompanied by β-amyloid deposition in some neurodegenerative diseases. We hypothesised that α-synuclein promotes β-amyloid production from APP. β-Amyloid levels and APP amyloidogenic processing were investigated in neuronal cell lines stably overexpressing wildtype and mutant α-synuclein. γ-Secretase activity and β-secretase expression were also measured. We show that α-synuclein expression induces β-amyloid secretion and amyloidogenic processing of APP in neuronal cell lines. Certain mutations of α-synuclein potentiate APP amyloidogenic processing. γ-Secretase activity was not enhanced by wildtype α-synuclein expression, however β-secretase protein levels were induced. Furthermore, a correlation between α-synuclein and β-secretase protein was seen in rat brain striata. Iron chelation abolishes the effect of α-synuclein on neuronal cell β-amyloid secretion, whereas overexpression of the ferrireductase enzyme Steap3 is robustly pro-amyloidogenic. We propose that α-synuclein promotes β-amyloid formation by modulating β-cleavage of APP, and that this is potentially mediated by the levels of reduced iron and oxidative stress.


Item Type Articles
CreatorsRoberts, H. L., Schneider, B. L. and Brown, D.
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Uncontrolled Keywordsmedicine(all),biochemistry, genetics and molecular biology(all),agricultural and biological sciences(all)
DepartmentsFaculty of Science > Biology & Biochemistry
ID Code56066


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