%0 Journal Article
%T Iron dysregulates APP processing accompanying with sAPP¦Á cellular retention and ¦Â-secretase inhibition in rat cortical neurons
%A Hai-yan Zhang
%A Wu-yan Chen
%A Xiao-tian Huang
%A Yu-ting Chen
%J Archive of "Acta Pharmacologica Sinica".
%D 2018
%R 10.1038/aps.2017.113
%X Amyloid precursor protein (APP) and iron both play pivotal roles in the central nervous system, but whether and how iron influences the processing of endogenous APP in neurons remain unclear. Here, we investigated the regulatory effects and underlying mechanisms of iron on non-amyloidogenic and amyloidogenic processing of APP in rat primary cortical neurons. Treatment of the neurons with ferric ammonium citrate (FAC, 100 ¦Ìmol/L) markedly facilitated the non-amyloidogenic processing of APP, as evidenced by a robust increase in ¦Á-secretase-derived carboxy-terminal fragment ¦Á (CTF¦Á). Furthermore, the distribution of sAPP¦Á was altered after iron treatment, and sAPP¦Á remained in the cellular lysates instead of being secreted into the extracellular milieu. Moreover, the levels of APP amyloidogenic products, including sAPP¦Â and A¦Â were both decreased. We further revealed that FAC did not alter the expression of ¦Â-secretase, but significantly suppressed its enzymatic activity in iron-treated neurons. In a cell-free ¦Â-secretase activity assay, FAC dose-dependently inhibited the activity of purified ¦Â-secretase with an IC50 value of 21.67 ¦Ìmol/L. Our data provide the first evidence that iron overload alters the neuronal sAPP¦Á distribution and directly inhibits ¦Â-secretase activity. These findings shed light on the regulatory mechanism of bio-metals on APP processing
%K iron
%K neurons
%K amyloid precursor protein
%K sAPP¦Á
%K ¦Â-amyloid
%K ¦Â-secretase
%K Alzheimer's disease
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800463/