Iron dysregulates APP processing accompanying with sAPPα cellular retention and β-secretase inhibition in rat cortical neurons

Chen, Yuting; Chen, Wu-yan; Huang, Xiaotian; Xu, Yechun; Zhang, Haiyan

doi:10.1038/aps.2017.113

Cited by 22 publications

(29 citation statements)

References 49 publications

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“…Therefore, iron accumulation in brain cells must be strictly regulated to maintain basic cellular function and avoid cytotoxicity. The evidence obtained confirms the role of the amyloid protein precursor in maintaining iron homeostasis in brain tissue (86). It has been demonstrated that the amyloid protein precursor and soluble amyloid protein precursor α facilitate iron outflow by stabilizing the iron exporter ferroportin 1 on the cell membrane (86,87).…”

Section: The Relationship Between Iron Dyshomeostasis and Amyloidogensupporting

confidence: 69%

“…The evidence obtained confirms the role of the amyloid protein precursor in maintaining iron homeostasis in brain tissue (86). It has been demonstrated that the amyloid protein precursor and soluble amyloid protein precursor α facilitate iron outflow by stabilizing the iron exporter ferroportin 1 on the cell membrane (86,87). In contrast, ablation of the amyloid protein precursor in neurons causes iron retention (87), while the knockout of the amyloid protein precursor in mice causes iron accumulation in the brain (86).…”

Section: The Relationship Between Iron Dyshomeostasis and Amyloidogensupporting

confidence: 62%

“…Both the amyloid protein precursor and iron play a key role in brain neurodegeneration due to Alzheimer' s disease and cerebral ischemia (59,(85)(86)(87)(88). Alzheimer' s disease is primarily characterized by the deposition of amyloid plaques and the formation of neurofibrillary tangles which co-localize with iron (88).…”

Section: The Relationship Between Iron Dyshomeostasis and Amyloidogenmentioning

confidence: 99%

“…Iron is gradually deposited in selected areas of the brain during Alzheimer' s disease, as well as in the course of ischemic neurodegeneration (59,(85)(86)(87)(88). In the brain, iron is present in neurons, oligodendrocytes, astroglia, and microglia cells.…”

Section: The Relationship Between Iron Dyshomeostasis and Amyloidogenmentioning

confidence: 99%

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Common Proteomic and Genomic Contribution to Ischemic Brain Damage and Alzheimer’s Disease

Pluta

Ułamek-Kozioł

Januszewski

et al. 2019

Alzheimer’s Disease

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Ischemic brain damage is associated with the deposition of folding proteins, such as all fragments of the amyloid protein precursor and tau protein, in the intra-and extracellular spaces of neurons. In this chapter, we summarize the protein changes associated with Alzheimer' s disease and their gene expression (amyloid protein precursor and tau protein) after cerebral ischemia and their role in the ischemic etiology of Alzheimer' s disease. Recent advances in understanding the ischemic etiology of Alzheimer' s disease have revealed dysregulation of amyloid protein precursors, β-secretase, presenilin 1 and 2, autophagy, mitophagy, apoptosis, and tau protein genes after ischemic brain injury. However, reduced expression of mRNA of the α-secretase in cerebral ischemia causes neurons to be less resistant to injury. In this chapter, we present the latest evidence that Alzheimer' s diseaserelated proteins and their genes play a key role in brain damage with ischemiareperfusion and that ischemic episode is an essential and leading provider of Alzheimer' s disease development. Understanding the underlying processes of linking Alzheimer' s disease-related proteins and their genes in brain ischemia

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Section: The Relationship Between Iron Dyshomeostasis and Amyloidogensupporting

confidence: 69%

Section: The Relationship Between Iron Dyshomeostasis and Amyloidogensupporting

confidence: 62%

Section: The Relationship Between Iron Dyshomeostasis and Amyloidogenmentioning

confidence: 99%

Section: The Relationship Between Iron Dyshomeostasis and Amyloidogenmentioning

confidence: 99%

See 2 more Smart Citations

Common Proteomic and Genomic Contribution to Ischemic Brain Damage and Alzheimer’s Disease

Pluta

Ułamek-Kozioł

Januszewski

et al. 2019

Alzheimer’s Disease

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“…In particular, this operates through a site in the APP 5′-UTR that binds iron response protein 1 (IRP1) 100,101,103 , interleukin 1 (IL1) 102,104,105 , and microRNA-346 100 . This "FeAR (Fe, APP, RNA) nexus" may also play a feedback role in αsecretase processing of APP, given that Fe also modulates α-secretase cleavage of APP 106 , specifically to increase sAPPα cellular retention and inhibit BACE1 activity 107 .…”

Section: Discussionmentioning

confidence: 99%

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

et al. 2020

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Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases-Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the nonamyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.

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Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance

Ayton

Portbury

Kalinowski

et al. 2021

Alzheimer's & Dementia

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Objective This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large‐scale emerging evidence. Background Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation. New/updated hypothesis We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation. Major challenges for the hypothesis While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele (APOE) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti‐ferroptotic/iron compound in AD patients. Linkage to other major theories Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well‐established consequence of aging and inflammation, which are major theories of disease pathogenesis.

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Iron dysregulates APP processing accompanying with sAPPα cellular retention and β-secretase inhibition in rat cortical neurons

Cited by 22 publications

References 49 publications

Common Proteomic and Genomic Contribution to Ischemic Brain Damage and Alzheimer’s Disease

Common Proteomic and Genomic Contribution to Ischemic Brain Damage and Alzheimer’s Disease

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance

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