Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention

Tsatsanis, Andrew; Wong, Bruce X.; Gunn, Adam P; Ayton, Scott; Bush, Ashley I.; Devos, David; Duce, James A.

doi:10.1038/s41380-020-0762-0

Cited by 62 publications

(64 citation statements)

References 33 publications

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“…Initially, it was thought that APP itself possessed ferroxidase activity since it possessed a site with homology to the ferroxidase catalytic site H-ferritin, but the oxidation measured was an artifact of contaminating phosphate buffer from the purification of the APP. Nonetheless, APP has been consistently reported to stabilize surface ferroportin, supporting a specific role in facilitating iron export from neurons (301)(302)(303)(304). Consistent with this proposed function, primary neuronal cultures from APP knockout mice retained iron compared to wild-type neurons (11,299).…”

Section: Ironmentioning

confidence: 71%

“…Presenilin, APP and apoE have each been associated with the being influenced or influencing the biological elements surveyed in this review. With the recognition of ferroptosis as a primordial form of regulated cell death, and with the discovery of pathogenic and protective APP mutations modulating the retention of neuronal iron in a way that might concord with jeopardy to the neuron (304), the stage is now set for a systematic investigation of the impact of FAD mutations on ferroptosis. If FAD mutations promote ferroptosis, this could be an instance of antagonistic pleiotropy, where the risk of later life AD is offset by the protection against cancer and infection.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the favorable Icelandic mutation generates more sAPPα, and, by stabilizing more ferroportin on the neuronal surface, promotes greater iron export than wild-type APP. These findings were recapitulated by pharmacological inhibition of α-secretase and βsecretase processing, respectively, and by other pharmacological approaches that modulated endocytotic processing pathways accordingly (304). Thus, these pathogenic or protective APP mutations might induce or protect against neurodegeneration through their impacts on neuronal iron retention, in which case the generation of Aβ is circumstantial rather than causative.…”

Section: Ironmentioning

confidence: 92%

“…Recently, amyloidogenic processing of APP was found to impact on iron export through stabilizing surface ferroportin (304). Two mutations of APP were studied-the pathogenic Italian mutation A673V and the protective Icelandic mutation A673T.…”

Section: Ironmentioning

confidence: 99%

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The essential elements of Alzheimer’s disease

Lei

Ayton

Bush

2021

Journal of Biological Chemistry

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188

132

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Treatments for Alzheimer’s disease (AD) directed against the prominent amyloid plaque neuropathology have yet to prove effective despite many phase 3 clinical trials. There are several other neurochemical abnormalities that occur in the Alzheimer’s disease brain that warrant renewed emphasis as potential therapeutic targets for this disease. Among those are the elementomic signatures of iron, copper, zinc, and selenium. Here we review these essential elements of Alzheimer’s disease for their broad potential to contribute to Alzheimer’s pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets.

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Section: Ironmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Ironmentioning

confidence: 92%

Section: Ironmentioning

confidence: 99%

See 2 more Smart Citations

The essential elements of Alzheimer’s disease

Lei

Ayton

Bush

2021

Journal of Biological Chemistry

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188

132

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“…334 Interestingly, this is not observed in non-amyloidogenic processing of APP, which also stabilizes FPN1. 334 Also in contrast to APP, which promotes iron efflux, Ab 42 -exposure increases ferritin production in astrocytes suggesting that Ab 42 may promote iron accumulation in astrocytes. 335 Such accumulation could be expected to affect the functioning of astrocytes, which would affect the health and functioning of neurons.…”

Section: Age-associated Neurodegenerative Diseasesmentioning

confidence: 97%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

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All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

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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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Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention

Cited by 62 publications

References 33 publications

The essential elements of Alzheimer’s disease

The essential elements of Alzheimer’s disease

Overdosing on iron: Elevated iron and degenerative brain disorders

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

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