An iron-export ferroxidase activity of β-amyloid protein precursor is inhibited by zinc in Alzheimer’s Disease

By J. Duce, Andrew Tsatsanis, M. Cater, S. James, Elysia L. Robb, K. Wikhe, S. L. Leong, Keyla Perez, T. Johanssen, M. Greenough and 11 more. Cell, 2010

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Summary Alzheimer’s Disease (AD) is complicated by pro-oxidant intraneuronal Fe2+ elevation as well as extracellular Zn2+ 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 Zn2+. Like ceruloplasmin, APP catalytically oxidizes Fe2+, loads Fe3+ 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 Fe2+ accumulation and oxidative stress in cortical neurons. Paralleling iron accumulation, APP ferroxidase activity in AD post-mortem neocortex is inhibited by endogenous Zn2+, which we demonstrate can originate from Zn2+-laden amyloid aggregates and correlates with Aβ burden. Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD.

View Paper: https://www.semanticscholar.org/paper/0d94937855ff63b9cc4705eed28ffdad334e35e3

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Citations in the corpus

Alzheimer's disease risk genes and mechanisms of disease pathogenesis (2014, unknown): “PICALM-deficient mice have no overt neurologic phenotypes but display abnormal iron metabolism, which has been implicated in APP processing (124).”
Ferroptosis: an iron-dependent form of nonapoptotic cell death. (2012, background): “Thus, for better or worse, the aberrantly elevated levels of iron that are observed in some cancer cells (Pinnix et al., 2010) and pathological neuronal populations (Duce et al., 2010; Lei et al., 2012) may predispose to ferroptotic death in situations of cystine or cysteine limitation.”
Oxidative stress and the amyloid beta peptide in Alzheimer’s disease (2017, background): “APP is also implicated in metal metabolism, as it can promote iron efflux of neurons [118], under the control of an iron-responsible element [119].”