Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

Masaldan, Shashank; Belaidi, Abdel Ali; Ayton, Scott; Bush, Ashley I.

doi:10.3390/ph12020093

Cited by 76 publications

(41 citation statements)

References 104 publications

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“…The main pathological features of AD are extracellular b-amyloid (Ab) deposition and neurofibrillary tangles caused by abnormal phosphorylation of intracellular Tau protein. There is evidence supporting that oxidative stress and iron metabolism disorder are associated with the progression of AD (Masaldan et al, 2019).…”

Section: Inhibitors Of Ferroptosismentioning

confidence: 99%

Ferroptosis and Its Potential Role in Human Diseases

et al. 2020

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Ferroptosis is a novel regulated cell death pattern discovered when studying the mechanism of erastin-killing RAS mutant tumor cells in 2012. It is an iron-dependent programmed cell death pathway mainly caused by an increased redox imbalance but with distinct biological and morphology characteristics when compared to other known cell death patterns. Ferroptosis is associated with various diseases including acute kidney injury, cancer, and cardiovascular, neurodegenerative, and hepatic diseases. Moreover, activation or inhibition of ferroptosis using a variety of ferroptosis initiators and inhibitors can modulate disease progression in animal models. In this review, we provide a comprehensive analysis of the characteristics of ferroptosis, its initiators and inhibitors, and the potential role of its main metabolic pathways in the treatment and prevention of various diseased states. We end the review with the current knowledge gaps in this area to provide direction for future research on ferroptosis.

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Section: Inhibitors Of Ferroptosismentioning

confidence: 99%

Ferroptosis and Its Potential Role in Human Diseases

et al. 2020

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“…The ability of iron to cycle through its oxidation states is fundamental to its diverse biological functions, but can also result in oxidative damage to cells. This has led to the evolution of tightly regulated homeostatic mechanisms to control iron availability and minimise toxicity (reviewed in [17]). Currently, gene expression patterns representing responses to iron dyshomeostasis are not well-characterised.…”

Section: Introductionmentioning

confidence: 99%

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Hin

Newman

Pederson

et al. 2020

Preprint

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Background: Iron trafficking and accumulation has been associated with Alzheimer's disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterised, making it difficult to explore these in existing datasets. Results: We identified sets of genes predicted to contain Iron Responsive Elements (IREs), and used these to explore iron dyshomeostasis responses in transcript datasets involving (1) cultured cells under iron overload and deficiency treatments, (2) post-mortem brain tissues from AD and other neuropathologies, (3) 5XFAD transgenic mice modelling AD pathologies, and (4) a zebrafish knock-in model of early-onset, familial AD (fAD). IRE gene sets were sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, we see changes in 3' IRE transcript abundance as amongst the earliest observable in zebrafish fAD-like brains and preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some 3' IRE transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead show decreased stability, indicating that this is not a generalizable paradigm. Conclusions: Our results reveal iron dyshomeostasis as a likely early driver of fAD and as able to distinguish AD from other brain pathologies. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis responses in different species, tissues, and conditions.

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“…Not only can iron and copper accumulation contribute to increases in oxidative stress and the potentiation of nerve cell death by oxytosis/ferroptosis [ 22 ] but recent studies suggest they may also may play roles in cellular senescence, a pro-inflammatory cell fate associated with age-related diseases, including AD [ 23 , 24 ]. Furthermore, iron and copper chelators have shown beneficial effects in animal models of AD [ 11 , 25 , 26 ] as well as some limited positive results in human AD patients [ 24 , 27 ]. However, these human results are tempered by the neurotoxicity associated with one of these compounds, cliquinol [ 28 , 29 ], as well as questions about its efficacy [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper

Maher

2020

Antioxidants

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Alterations occur in the homeostasis of the transition metals iron (Fe2+) and copper (Cu2+) during aging and these are further amplified in neurodegenerative diseases, including Alzheimer’s disease (AD). These observations suggest that the most effective drug candidates for AD might be those that can reduce these alterations. The flavonoid fisetin has both neuroprotective and anti-inflammatory activity both in vitro and in vivo and can bind both iron and copper suggesting that its chelating activity might play a role in its beneficial effects. To test this idea, the effects of iron and copper on both the neuroprotective and anti-inflammatory activities of fisetin were examined. It is shown that while fisetin can reduce the potentiation of cell death by iron and copper in response to treatments that lower glutathione levels, it is much less effective when the metals are combined with other inducers of oxidative stress. In addition, iron but not copper reduces the anti-inflammatory effects of fisetin in a dose-dependent manner. These effects correlate with the ability of iron but not copper to block the induction of the antioxidant transcription factor, Nrf2, by fisetin. In contrast, although the flavanone sterubin also binds iron, the metal has no effect on sterubin’s ability to induce Nrf2 or protect cells from toxic or pro-inflammatory insults. Together, these results suggest that while iron and copper binding could contribute to the beneficial effects of neuroprotective compounds in the context of neurodegenerative diseases, the consequences of this binding need to be fully examined for each compound.

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Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

Cited by 76 publications

References 104 publications

Ferroptosis and Its Potential Role in Human Diseases

Ferroptosis and Its Potential Role in Human Diseases

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper

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