Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine/glutamate antiporter in Alzheimer’s disease: Evidence of ferroptosis

Ashraf, Azhaar; Jeandriens, Jérôme; Parkes, Harold G.; So, Po‐Wah

doi:10.1016/j.redox.2020.101494

Cited by 207 publications

(147 citation statements)

References 68 publications

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“…We predict that these proteins may affect levels of heme and iron proteins, as iron is required for seeding and aggregation of tau [67], of α-synuclein [68], and, indirectly, of TDP43 [69,70]. We have recently provided evidence to support the presence of a recently discovered iron-dependent cell death, ferroptosis, in AD [71]. Iron chelation has shown promise against AD and PD in preclinical studies and clinical trials and has therapeutic potential to extinguish iron-dependent ferroptosis, a mechanism proposed to contribute to neurodegeneration [67].…”

Section: Discussionmentioning

confidence: 93%

Plasma transferrin and hemopexin are associated with altered Aβ uptake and cognitive decline in Alzheimer’s disease pathology

et al. 2020

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Background: Heme and iron homeostasis is perturbed in Alzheimer's disease (AD); therefore, the aim of the study was to examine the levels and association of heme with iron-binding plasma proteins in cognitively normal (CN), mild cognitive impairment (MCI), and AD individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohorts. Methods: Non-targeted proteomic analysis by high-resolution mass spectrometry was performed to quantify relative protein abundances in plasma samples from 144 CN individuals from the AIBL and 94 CN from KARVIAH cohorts and 21 MCI and 25 AD from AIBL cohort. ANCOVA models were utilized to assess the differences in plasma proteins implicated in heme/iron metabolism, while multiple regression modeling (and partial correlation) was performed to examine the association between heme and iron proteins, structural neuroimaging, and cognitive measures. Results: Of the plasma proteins implicated in iron and heme metabolism, hemoglobin subunit β (p = 0.001) was significantly increased in AD compared to CN individuals. Multiple regression modeling adjusted for age, sex, APOEε4 genotype, and disease status in the AIBL cohort revealed lower levels of transferrin but higher levels of hemopexin associated with augmented brain amyloid deposition. Meanwhile, transferrin was positively associated with hippocampal volume and MMSE performance, and hemopexin was negatively associated with CDR scores. Partial correlation analysis revealed lack of significant associations between heme/iron proteins in the CN individuals progressing to cognitive impairment. Conclusions: In conclusion, heme and iron dyshomeostasis appears to be a feature of AD. The causal relationship between heme/iron metabolism and AD warrants further investigation.

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Section: Discussionmentioning

confidence: 93%

Plasma transferrin and hemopexin are associated with altered Aβ uptake and cognitive decline in Alzheimer’s disease pathology

et al. 2020

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“…However, the treatment of Aβ alone does not prevent the progression of AD, suggesting the presence of other factors [64]. Recent research has found evidence of ferroptosis in AD, including iron dyshomeostasis, increased expression of xCT and lipid peroxidation, coexistent with an augmented excitatory glutamate:inhibitory GABA ratio [65].…”

Section: The Role Of Ferroptosis In Neurodegenerative Diseasesmentioning

confidence: 99%

Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases

et al. 2020

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Background: Neurodegenerative diseases are characterized by a gradual decline in motor and/or cognitive function caused by the selective degeneration and loss of neurons in the central nervous system, but their pathological mechanism is still unclear. Previous research has revealed that many forms of cell death, such as apoptosis and necrosis, occur in neurodegenerative diseases. Research in recent years has noticed that there is a new type of cell death in neurodegenerative diseases: ferroptosis. An increasing body of literature provides evidence for an involvement of ferroptosis in neurodegenerative diseases. Summary: In this article, we review a new form of cell death in neurodegenerative diseases: ferroptosis. Ferroptosis is defined as an iron-dependent form of regulated cell death, which occurs through the lethal accumulation of lipid-based reactive oxygen species when glutathione-dependent lipid peroxide repair systems are compromised. Several salient and established features of neurodegenerative diseases (including lipid peroxidation and iron dyshomeostasis) are consistent with ferroptosis, which means that ferroptosis may be involved in the progression of neurodegenerative diseases. In addition, as the center of energy metabolism in cells, mitochondria are also closely related to the regulation of iron homeostasis in the nervous system. At the same time, neurodegenerative diseases are often accompanied by degeneration of mitochondrial activity. Mitochondrial damage has been found to be involved in lipid peroxidation and iron dyshomeostasis in neurodegenerative diseases. Key Messages: Based on the summary of the related mechanisms of ferroptosis, we conclude that mitochondrial damage may affect neurodegenerative diseases by regulating many aspects of ferroptosis, including cell metabolism, iron dyshomeostasis, and lipid peroxidation.

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“…Currently approved therapies are only symptomatic, with limited improvements in memory. Efforts to understand the mechanisms underlying cell damage and death in AD have highlighted the detrimental effects of excessive lipid peroxidation [ 3 , 4 ]. Moreover, it is likely to be an early feature of the disease, as post-mortem brain samples from subjects with mild cognitive impairment already show increased levels of lipid peroxidation, which are maintained throughout disease progression [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

CMS121, a fatty acid synthase inhibitor, protects against excess lipid peroxidation and inflammation and alleviates cognitive loss in a transgenic mouse model of Alzheimer's disease

et al. 2020

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The oxidative degradation of lipids has been shown to be implicated in the progression of several neurodegenerative diseases and modulating lipid peroxidation may be efficacious for treating Alzheimer’s disease (AD). This hypothesis is strengthened by recent findings suggesting that oxytosis/ferroptosis, a cell death process characterized by increased lipid peroxidation, plays an important role in AD-related toxicities. CMS121 is a small molecule developed against these aspects of neurodegeneration. Here we show that CMS121 alleviates cognitive loss, modulates lipid metabolism and reduces inflammation and lipid peroxidation in the brains of transgenic AD mice. We identify fatty acid synthase (FASN) as a molecular target of CMS121 and demonstrate that modulating lipid metabolism through the inhibition of FASN protects against several AD-related toxicities. These results support the involvement of lipid peroxidation and perturbed lipid metabolism in AD pathophysiology and propose FASN as a target in AD-associated toxicities.

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Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine/glutamate antiporter in Alzheimer’s disease: Evidence of ferroptosis

Cited by 207 publications

References 68 publications

Plasma transferrin and hemopexin are associated with altered Aβ uptake and cognitive decline in Alzheimer’s disease pathology

Plasma transferrin and hemopexin are associated with altered Aβ uptake and cognitive decline in Alzheimer’s disease pathology

Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases

CMS121, a fatty acid synthase inhibitor, protects against excess lipid peroxidation and inflammation and alleviates cognitive loss in a transgenic mouse model of Alzheimer's disease

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