Amyloidogenic processing of Alzheimer's disease β-amyloid precursor protein induces cellular iron retention
- PMID: 32444869
- DOI: 10.1038/s41380-020-0762-0
Amyloidogenic processing of Alzheimer's disease β-amyloid precursor protein induces cellular iron retention
Abstract
The proteolytic cleavage of β-amyloid precursor protein (APP) to form the amyloid beta (Aβ) peptide is related to the pathogenesis of Alzheimer's disease (AD) because APP mutations that influence this processing either induce familial AD or mitigate the risk of AD. Yet Aβ formation itself may not be pathogenic. APP promotes neuronal iron efflux by stabilizing the cell-surface presentation of ferroportin, the only iron export channel of cells. Mislocalization of APP can promote iron retention, thus we hypothesized that changes in endocytotic trafficking associated with altered APP processing could contribute to the neuronal iron elevation and oxidative burden that feature in AD pathology. Here, we demonstrate, using genetic and pharmacological approaches, that endocytotic amyloidogenic processing of APP impairs iron export by destabilizing ferroportin on the cell surface. Conversely, preferential non-amyloidogenic processing of APP at the cell surface promotes ferroportin stabilization to decrease intraneuronal iron. A new Aβ-independent hypothesis emerges where the amyloidogenic processing of APP, combined with age-dependent iron elevation in the tissue, increases pro-oxidant iron burden in AD.
Similar articles
-
The acute phase protein lactoferrin is a key feature of Alzheimer's disease and predictor of Aβ burden through induction of APP amyloidogenic processing.Mol Psychiatry. 2021 Oct;26(10):5516-5531. doi: 10.1038/s41380-021-01248-1. Epub 2021 Aug 16. Mol Psychiatry. 2021. PMID: 34400772 Free PMC article.
-
Alzheimer's disease.Subcell Biochem. 2012;65:329-52. doi: 10.1007/978-94-007-5416-4_14. Subcell Biochem. 2012. PMID: 23225010 Review.
-
Differential regulation of amyloid precursor protein sorting with pathological mutations results in a distinct effect on amyloid-β production.J Neurochem. 2014 Nov;131(4):407-12. doi: 10.1111/jnc.12829. Epub 2014 Aug 13. J Neurochem. 2014. PMID: 25053581
-
Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence.J Biol Chem. 2016 Nov 11;291(46):24041-24053. doi: 10.1074/jbc.M116.744722. Epub 2016 Sep 29. J Biol Chem. 2016. PMID: 27687728 Free PMC article.
-
Therapeutic approaches to Alzheimer's disease through stimulating of non-amyloidogenic processing of amyloid precursor protein.Eur Rev Med Pharmacol Sci. 2016 Jun;20(11):2389-403. Eur Rev Med Pharmacol Sci. 2016. PMID: 27338066 Review.
Cited by
-
Regulation of cardiac ferroptosis in diabetic human heart failure: uncovering molecular pathways and key targets.Cell Death Discov. 2024 Jun 1;10(1):268. doi: 10.1038/s41420-024-02044-w. Cell Death Discov. 2024. PMID: 38824159 Free PMC article.
-
MST1 selective inhibitor Xmu-mp-1 ameliorates neuropathological changes in a rat model of sporadic Alzheimer's Disease by modulating Hippo-Wnt signaling crosstalk.Apoptosis. 2024 May 17. doi: 10.1007/s10495-024-01975-0. Online ahead of print. Apoptosis. 2024. PMID: 38760516
-
Monocytes release cystatin F dimer to associate with Aβ and aggravate amyloid pathology and cognitive deficits in Alzheimer's disease.J Neuroinflammation. 2024 May 10;21(1):125. doi: 10.1186/s12974-024-03119-2. J Neuroinflammation. 2024. PMID: 38730470 Free PMC article.
-
The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases.Int J Mol Sci. 2024 Apr 12;25(8):4269. doi: 10.3390/ijms25084269. Int J Mol Sci. 2024. PMID: 38673855 Free PMC article. Review.
-
Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases.Front Cell Neurosci. 2024 Mar 7;18:1359453. doi: 10.3389/fncel.2024.1359453. eCollection 2024. Front Cell Neurosci. 2024. PMID: 38515787 Free PMC article. Review.
References
-
- Koo EH, Squazzo SL. Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem. 1994;269:17386–9. - DOI
-
- Udayar V, Buggia-Prevot V, Guerreiro RL, Siegel G, Rambabu N, Soohoo AL, et al. A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of beta-amyloid production. Cell Rep. 2013;5:1536–51. - DOI
-
- Ehehalt R, Keller P, Haass C, Thiele C, Simons K. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol. 2003;160:113–23. - DOI
-
- Sannerud R, Declerck I, Peric A, Raemaekers T, Menendez G, Zhou L, et al. ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci USA. 2011;108:E559–68. - DOI
-
- Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488:96–9. - DOI
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical