Journal article

alpha-Synuclein increases beta-amyloid secretion by promoting beta-/gamma-secretase processing of APP

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


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