Ferroptosis as a mechanism of neurodegeneration in Alzheimer's disease

Jakaria, Md.; Belaidi, Abdel Ali; Bush, Ashley I.; Ayton, Scott

doi:10.1111/jnc.15519

Cited by 113 publications

(73 citation statements)

References 328 publications

(390 reference statements)

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“…Based on these results, Feng et al concluded that microglial activation after SCI caused ferroptosis of motor neurons and impaired the recovery of motor function [38]. Evidence suggests that ferroptosis is associated with multiple neurologic conditions, making it an increasingly important mechanism of CNS degeneration with microglial activation or polarization [39][40][41]. Consequently, targeting the proferroptosis effect on microglia in the treatment of neural diseases should consider the anti-inflammatory effect as well as the proferroptosis effect to yield optimum results [42].…”

Section: Discussionmentioning

confidence: 99%

Wild Bitter Melon Extract Abrogates Hypoxia-Induced Cell Death via the Regulation of Ferroptosis, ER Stress, and Apoptosis in Microglial BV2 Cells

Lin

Hsieh

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Microglial cells are well-known phagocytic cells that are resistant to the central nervous system (CNS) and play an important role in the maintenance of CNS homeostasis. Activated microglial cells induce neuroinflammation under hypoxia and typically cause neuronal damage in CNS diseases. In this study, we propose that wild bitter melon extract (WBM) has a protective effect on hypoxia-induced cell death via regulation of ferroptosis, ER stress, and apoptosis. The results demonstrated that hypoxia caused microglial BV-2 the accumulation of lipid ROS, ferroptosis, ER stress, and apoptosis. In this study, we investigated the pharmacological effects of WBM on BV-2 cells following hypoxia-induced cell death. The results indicated that WBM reversed hypoxia-downregulated antiferroptotic molecules Gpx4 and SLC7A11, as well as upregulated the ER stress markers CHOP and Bip. Moreover, WBM alleviated hypoxia-induced apoptosis via the regulation of cleaved-caspase 3, Bax, and Bcl-2. Our results suggest that WBM may be a good candidate for preventing CNS disorders in the future.

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Section: Discussionmentioning

confidence: 99%

Wild Bitter Melon Extract Abrogates Hypoxia-Induced Cell Death via the Regulation of Ferroptosis, ER Stress, and Apoptosis in Microglial BV2 Cells

Lin

Hsieh

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Cerebral Fe accumulation in AD was already described in the early 1950s [303]. Lately, Fe accumulation and dyshomeostasis in AD have attracted increasing attention as part of the pathogenesis and as a therapeutic target in recent reviews [304][305][306]. More recent studies of AD brains with advanced techniques (i.a., laser ablation-inductively coupled plasmamass spectrometry) have shown accumulation of Fe in the frontal cortex and hippocampus apparently together with Aβ and p-tau deposits [117,[307][308][309][310][311][312].…”

Section: Iron Accumulation and Pathology In Sporadic Neurodegenerativ...mentioning

confidence: 99%

Cerebral Iron Deposition in Neurodegeneration

et al. 2022

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Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

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“…Despite characteristic pathological hallmarks of AD, including Aβ plaque and neurofibrillary tangles, the mechanism of neurodegeneration remains largely obscure. Since phospholipid peroxidation is apparent in AD patient brain samples, a growing body of evidence indicates the involvement of ferroptotic mechanisms in the pathogenesis of AD [ 154 ]. Elevated iron concentration was found in clinic-pathological examinations of AD cases many decades ago and targeting iron has been proposed as a disease-modifying therapy for AD [ 155 ].…”

Section: Ferroptosismentioning

confidence: 99%

CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases

et al. 2022

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A single paragraph of about 200 words maximum. Neurodegenerative diseases (ND), such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, pose a global challenge in the aging population due to the lack of treatments for their cure. Despite various disease-specific clinical symptoms, ND have some fundamental common pathological mechanisms involving oxidative stress and neuroinflammation. The present review focuses on the major causes of central nervous system (CNS) redox homeostasis imbalance comprising mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Mitochondrial disturbances, leading to reduced mitochondrial function and elevated reactive oxygen species (ROS) production, are thought to be a major contributor to the pathogenesis of ND. ER dysfunction has been implicated in ND in which protein misfolding evidently causes ER stress. The consequences of ER stress ranges from an increase in ROS production to altered calcium efflux and proinflammatory signaling in glial cells. Both pathological pathways have links to ferroptotic cell death, which has been implicated to play an important role in ND. Pharmacological targeting of these pathological pathways may help alleviate or slow down neurodegeneration.

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Ferroptosis as a mechanism of neurodegeneration in Alzheimer's disease

Cited by 113 publications

References 328 publications

Wild Bitter Melon Extract Abrogates Hypoxia-Induced Cell Death via the Regulation of Ferroptosis, ER Stress, and Apoptosis in Microglial BV2 Cells

Wild Bitter Melon Extract Abrogates Hypoxia-Induced Cell Death via the Regulation of Ferroptosis, ER Stress, and Apoptosis in Microglial BV2 Cells

Cerebral Iron Deposition in Neurodegeneration

CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases

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