Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Sep-Oct;12(5A):1548-50.
doi: 10.1111/j.1582-4934.2008.00356.x. Epub 2008 May 1.

A potential pathogenetic role of iron in Alzheimer's disease

Laura Silvestri  1 , Clara Camaschella
Affiliations

A potential pathogenetic role of iron in Alzheimer's disease

Laura Silvestri et al. J Cell Mol Med. 2008 Sep-Oct.

Abstract

The role of iron in the pathogenesis of Alzheimer's disease (AD) is still unclear, despite the evidence that it accumulates in the same brain regions characterized by the amyloid beta peptide (Abeta) accumulation. Here we propose that iron directly influences the Abeta production through the modulation of furin, a proconvertase involved in the regulation of the alpha-secretase-dependent processing of the amyloid protein precursor (APP).

PubMed Disclaimer

Figures

1
1
Schematic representation of the proposed mechanisms leading to increased iron and iron mediated mechanisms of Aβ upregulation. The initial iron accumulation downregulates furin, impairing the processing of ADAM10 and TACE, the two α-secretases involved in sAPP production. Since the activity of α- and β-secretases are tightly balanced, due to the close proximity of their consensus cleavage sites, reduction in α-secretase activity increases the Aβ production, through β- and γ-secretases. Iron accumulation in the cell increases the reactive oxygen species (ROS) production, which upregulates TIMP2, an inhibitor of α-secretase, and shifts the cytoplasmic aconitase to IRP1, giving a wrong signal of iron deficiency and stimulating the cells to enhance iron uptake. The effects mediated by ROS create a vicious circle, which amplify the α-secretase activity reduction and increment the Aβ production.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Tachida Y, Nakagawa K, Saito T, Saido TC, Honda T, Saito Y, Murayama S, Endo T, Sakaguchi G, Kato A, Kitazume S, Hashimoto Y. Interleukin-1beta up-regu-lates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production. J Neurochem. 2008;104:1387–93. - PubMed
    1. Anders A, Gilbert S, Garten W, Postina R, Fahrenholz F. Regulation of the alpha-sec-retase ADAM10 by its prodomain and pro-protein convertases. FASEB J. 2001;15:1837–9. - PubMed
    1. Hwang EM, Kim SK, Sohn JH, Lee JY, Kim Y, Kim YS, Mook-Jung I. Furin is an endogenous regulator of alpha-secretase associated APP processing. Biochem Biophys Res Commun. 2006;349:654–9. - PubMed
    1. Bennett BD, Denis P, Haniu M, Teplow DB, Kahn S, Louis J-C, Citron M, Vassar R. A furin-like convertase nediates propep-tide cleavage of BACE, the Alzheimer's beta-secretase. J Biol Chem. 2000;275:37712–7. - PubMed
    1. Creemers JWM, Dominguez DI, Plets E, Serneels L, Taylor NA, Multhaup G, Craessaerts K, Annaert W, De Strooper B. Processing of beta-secretase by furin and other members of the proprotein con-vertase family. J Biol Chem. 2001;276:4211–7. - PubMed