Iron-Export Ferroxidase Activity of β-Amyloid Precursor Protein Is Inhibited by Zinc in Alzheimer's Disease

Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3052, Australia.
Cell (Impact Factor: 32.24). 09/2010; 142(6):857-67. DOI: 10.1016/j.cell.2010.08.014
Source: PubMed


Alzheimer's Disease (AD) is complicated by pro-oxidant intraneuronal Fe(2+) elevation as well as extracellular Zn(2+) accumulation within amyloid plaque. We found that the AD β-amyloid protein precursor (APP) possesses ferroxidase activity mediated by a conserved H-ferritin-like active site, which is inhibited specifically by Zn(2+). Like ceruloplasmin, APP catalytically oxidizes Fe(2+), loads Fe(3+) into transferrin, and has a major interaction with ferroportin in HEK293T cells (that lack ceruloplasmin) and in human cortical tissue. Ablation of APP in HEK293T cells and primary neurons induces marked iron retention, whereas increasing APP695 promotes iron export. Unlike normal mice, APP(-/-) mice are vulnerable to dietary iron exposure, which causes Fe(2+) accumulation and oxidative stress in cortical neurons. Paralleling iron accumulation, APP ferroxidase activity in AD postmortem neocortex is inhibited by endogenous Zn(2+), which we demonstrate can originate from Zn(2+)-laden amyloid aggregates and correlates with Aβ burden. Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD.

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    • "Linked reports also confirmed that amyloid-␤ protein precursor (A␤PP) mRNA has an iron-responsive element RNA stem loop in its 5'-UTR and the translation of A␤PP is under the regulation of iron [17] [18]. One key 2010 study suggested that A␤PP protein, in excess, can control iron export from neurons in the brain [19]. These papers lent support to the earlier genetic reports that linked mutations of iron-related genes, including transferrin , with the risk of AD, thus suggesting that iron mis-management could contribute to the initiation and progression of brain disorders [20] [21] [22] [23]. "

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    • "For example, increased levels of the iron importer DMT1 has been observed in the cortex and hippocampus of AD transgenic models (Zheng et al., 2009), whereas levels of the iron storage protein ferritin are increased in reactive microglia present both in and around senile plaques (Connor et al., 1992). Similarly, AD brains show decreased levels of the iron exporter ferroportin 1 (Fpn1) (Crespo et al., 2014; Raha et al., 2013) and ferroxidase activity of APP (Duce et al., 2010) together with reduced levels of ceruloplasmin (Connor et al., 1993), which are required for the release of iron from cells. All these changes in iron homeostasis proteins clearly point to an iron accumulation phenotype, with an evident risk for the development of metal-based neurodegeneration. "
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    • "The longer isoforms of APP additionally include a Kunitz-type protease inhibitor domain (KPI) between AcD and E2 (Reinhard et al., 2005). Several additional physiological functions have been described for APP, including its function as an atypical ligand of DR6 (Kuester et al., 2011; Nikolaev et al., 2009); as a receptor (Ho and Sudhof, 2004); as a cell–cell-and cell–ECM– adhesion molecule (Breen et al., 1991; Soba et al., 2005); and as a protein for metal binding and transport (Bush et al., 1993; Duce et al., 2010; Hesse et al., 1994; Honarmand Ebrahimi et al., 2013). Recently, a novel metal binding site was described to reside within the E2 domain (Dahms et al., 2012), which is different from the widely discussed metal-binding site within the CuBD of E1 (Kong et al., 2007) and seems to act as conformational switch regulating the metal-dependent properties of APP. "
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    ABSTRACT: The amyloid precursor protein (APP) and its cellular processing are believed to be centrally involved in the etiology of Alzheimer’s disease (AD). In addition, many physiological functions have been described for APP, including a role in cell-cell- and cell-ECM-adhesion as well as in axonal outgrowth. We show here the molecular determinants of the oligomerization/dimerization of APP, which is central for its cellular (mis)function. Using size exclusion chromatography (SEC), dynamic light scattering and SEC-coupled static light scattering we demonstrate that the dimerization of APP is energetically induced by a heparin mediated dimerization of the E1 domain, which results in a dimeric interaction of E2. We also show that the acidic domain (AcD) interferes with the dimerization of E1 and propose a model where both, cis- and trans-dimerization occur dependent on cellular localization and function.
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