Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the ...accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.
Alzheimer's disease (AD) is the most prevalent form of dementia, with complex pathophysiology that is not fully understood. While β‐amyloid plaque and neurofibrillary tangles define the pathology of ...the disease, the mechanism of neurodegeneration is uncertain. Ferroptosis is an iron‐mediated programmed cell death mechanism characterised by phospholipid peroxidation that has been observed in clinical AD samples. This review will outline the growing molecular and clinical evidence implicating ferroptosis in the pathogenesis of AD, with implications for disease‐modifying therapies.
Ferroptosis, an iron‐mediated programmed cell death, is a possible mechanism of neuronal cell death in Alzheimer's disease that is propagated by increased PUFAs and labile iron levels and decreased GSH and antioxidant defense. Several risk factors such as stroke and TBI may lead to lipid peroxidation. Iron chelators such as deferiprone and lipophilic antioxidants such as N‐acetylcysteine, CuIIATSM and vitamin E protect against lipid peroxidation, and they may have potential therapeutic value to prevent ferroptotic stress in the progression of Alzheimer's disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A putative role for iron in driving Alzheimer's disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish ...how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ
/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.
Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ
/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort.
In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%-40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-.
CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.
Iron dyshomeostasis is a feature of Alzheimer's disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) ...and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies ...suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo.
We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies.
Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone.
Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Genetic variations to apolipoprotein E (apoE) underlie the strongest risk for Alzheimer´s disease (AD) after aging but it is not yet known how apoE confers risk for AD. While most research ...is focusing on dysregulations associated with the presence of the risk allele of apoE, several aspects of apoE biology remain poorly understood. In particular, the physiological relevance of apoE interaction with members of the low‐density lipoprotein (LDL) receptor gene family is not well understood.
Method
Ferroptosis was induced in the N27 neuronal cell model of ferroptosis using multiple agents (erastin, RSL3, iron, cysteine depletion). Genetic variants of apolipoprotein E receptor 2 (apoER2) were generated via site‐directed mutagenesis and expressed in N27 neurons. The severity of ferroptosis was measured by several toxicity assays (MTT, LDH) and lipid peroxide probe (C11BODIPY). The association between apoER2 polymorphism and cognition were investigated in two longitudinal studies: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL).
Result
We recently reported that apoE is a potent inhibitor of ferroptosis in neuronal cells in a mechanism that involves a receptor‐mediated activation of the PI3K/AKT signaling pathway. In this study, we identified genetic variants of apoER2 (also known as LRP8, a member of the LDL receptor family) that were associated with slower cognitive decline in clinical cohorts of AD. In preliminary work, we show that one apoER2 variant was associated with an increased protection from ferroptosis in an apoE‐dependent process.
Conclusion
We present evidence for a biological role of apoER2 and its genetic variation on pathologies associated with Alzheimer’s disease, which may help develop new diagnostic and therapeutic approaches towards the disease.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The emergence of ferroptosis as a cell death pathway associated with brain disorders including stroke and neurodegenerative diseases emphasizes the need to develop therapeutics able to target the ...brain and to protect neurons from ferroptotic death. Selenium plays an essential role in reducing lipid peroxidation generated during ferroptosis through its incorporation into the catalytic site of glutathione peroxidase 4. Here, we compared the anti-ferroptotic activity of several organic and inorganic selenium compounds: methylselenocysteine, selenocystine, selenomethionine, selenocystamine, ebselen, sodium selenite, and sodium selenate. All were effective against erastin- and RSL3-induced ferroptosis in vitro. We characterized the ability of the selenium compounds to release selenium and boost glutathione peroxidase expression and activity. Based on our results, we selected organic selenium compounds of similar characteristics and investigated their effectiveness in protecting against neuronal death in vivo using the cerebral ischemia–reperfusion injury mouse model. We found that pretreatment with methylselenocysteine or selenocystamine provided protection from ischemia–reperfusion neuronal damage in vivo. These data support the use of ferroptosis inhibitors for treatment and select selenium compounds for prevention of neuronal damage in ischemic stroke and other diseases of the brain where ferroptosis is implicated.
Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer's disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD ...CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC
≈ 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer's disease was stronger among those with the adverse APOE-ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele's heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Apolipoprotein E (ApoE) plays a crucial role in the homeostatic control of lipids in both the periphery and the central nervous system (CNS). In humans, ApoE exists in three different isoforms: ε2, ...ε3 and ε4. ApoE ε3 is the most common isoform, while the ε4 isoform confers the greatest genetic risk for Alzheimer’s disease (AD). However, the mechanisms underlying how ApoE contributes to the pathogenesis of AD are still debated. ApoE has been shown to impact amyloid β (Aβ) deposition and clearance in the brain. ApoE also has Aβ-independent pathways in AD, which has led to the discovery of new roles of ApoE ranging from mitochondria dysfunction to, most recently, iron metabolism. Here, we review the role of ApoE in health and in AD, with the view of identifying therapeutic approaches that could prevent the risk associated with the ε4 isoform.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer's disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical ...iron burden predicts Alzheimer's disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin γ-secretase activity cleaves Notch-1 to signal LRP8 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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