Premium
Iron Levels Modulate α‐Secretase Cleavage of Amyloid Precursor Protein
Author(s) -
Bodovitz Steven,
Falduto Michael T.,
Frail Donald E.,
Klein William L.
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.64010307.x
Subject(s) - amyloid precursor protein , chemistry , biochemistry , ferritin , amyloid precursor protein secretase , microbiology and biotechnology , biology , alzheimer's disease , medicine , disease
The amyloid precursor protein (APP) is a membrane‐spanning glycoprotein that is the source of βA4 peptides, which aggregate in Alzheimer's disease to form senile plaques. APP is cleaved within the βA4 sequence to release a soluble N‐terminal derivative (APP sol ), which has a wide range of trophic and protective functions. In the current study we have examined the hypothesis that iron availability may modulate expression or processing of APP, whose mRNA contains, based on sequence homology, a putative iron response element (IRE). Radiolabeled APP and its catabolites were precipitated from lysates and conditioned medium of stably transfected HEK 293 cells using antibodies selective for C‐terminal, βA4, and N‐terminal domains. The relative abundance of the different APP catabolites under different conditions of iron availability was determined by quantitative densitometry after separation by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis. The data show a specific effect on the production of APP sol . Using standard conditions previously established for IRE studies, it was found that iron chelation reduces APP sol production, whereas iron level elevation augments it. No changes were observed in levels of immature and mature APP holoprotein or in the C‐terminal α‐secretase derivative C83, βA4, and p3 peptides. The specificity for modulatory changes in APP sol suggests that iron acts at the level of α‐secretase activity. In addition to its modulatory effects, iron at very high levels was found to inhibit maturation of APP and production of its downstream catabolites without blocking formation of immature APP. The data establish a potential physiological role for iron in controlling the processing of APP. If APP sol were to function trophically, as suggested by other studies, the current conclusion suggests that changes in iron and iron‐regulating proteins in Alzheimer's disease could contribute to neuronal degeneration by decreasing the production of APP sol .