Ferroptosis is an iron- and lipid peroxidation (LPO)-mediated programmed cell death type. Recently, mounting evidence has indicated the involvement of ferroptosis in neurodegenerative diseases, especially in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and so on. Treating ferroptosis presents opportunities as well as challenges for neurodegenerative diseases. This review provides a comprehensive overview of typical features of ferroptosis and the underlying mechanisms that contribute to its occurrence, as well as their implications in the pathogenesis and advancement of major neurodegenerative disorders. Meanwhile, we summarize the utilization of ferroptosis inhibition in both experimental and clinical approaches for the treatment of major neurodegenerative disorders. In addition, we specifically summarize recent advances in developing therapeutic means targeting ferroptosis in these diseases, which may guide future approaches for the effective management of these devastating medical conditions. 

Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases

The incidence of neurological diseases, such as Parkinson’s disease, Alzheimer’s disease and stroke, is increasing. An increasing number of studies have correlated these diseases with brain iron overload and the resulting oxidative damage. Brain iron deficiency has also been closely linked to neurodevelopment. These neurological disorders seriously affect the physical and mental health of patients and bring heavy economic burdens to families and society. Therefore, it is important to maintain brain iron homeostasis and to understand the mechanism of brain iron disorders affecting reactive oxygen species (ROS) balance, resulting in neural damage, cell death and, ultimately, leading to the development of disease. Evidence has shown that many therapies targeting brain iron and ROS imbalances have good preventive and therapeutic effects on neurological diseases. This review highlights the molecular mechanisms, pathogenesis and treatment strategies of brain iron metabolism disorders in neurological diseases.

/pdf/brain-iron-metabolism-redox-balance-and-neurological-grvg0uj1.pdf

Brain Iron Metabolism, Redox Balance and Neurological Diseases

Alzheimer's disease (AD) is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors, accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain. At the cellular and molecular levels, the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities, compromised bioenergetics, impaired lipid metabolism, and reduced overall metabolic capacity, which lead to abnormal neural network activity and impaired neuroplasticity, thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles. The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise. Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state, inhibit different pathophysiological molecular pathways associated with AD, influence the pathological process of AD, and exert a protective effect, there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise. Here, we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD, including glucose metabolism, lipid metabolism, Aβ metabolism and transport, iron metabolism and tau pathology. How metabolic states influence brain health is also presented. A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions. 

/pdf/brain-metabolism-in-alzheimers-disease-biological-mechanisms-s4t9ix9a.pdf

Brain metabolism in Alzheimer’s disease: biological mechanisms of exercise

Lifetime risk of Alzheimer disease (AD) dementia is twofold higher in women compared with men, and low estrogen levels in postmenopause have been suggested as a possible contributor. We examined 3 ER (GPER1, ER2, and ER1) variants in association with AD traits as an indirect method to test the association between estrogen and AD in women. Although the study focus was on women, in a comparison, we separately examined ER molecular variants in men.Participants were followed for an average of 10 years in one of the 2 longitudinal clinical pathologic studies of aging. Global cognition was assessed using a composite score derived from 19 neuropsychological tests' scores. Postmortem pathologic assessment included examination of 3 AD (amyloid-β and tau tangles determined by immunohistochemistry, and a global AD pathology score derived from diffuse and neurotic plaques and neurofibrillary tangle count) and 8 non-AD pathology indices. ER molecular genomic variants included genotyping and examining ER DNA methylation and RNA expression in brain regions including the dorsolateral prefrontal cortex (DLPFC) that are major players in cognition and often have AD pathology.The mean age of women (N = 1711) at baseline was 78.0 (SD = 7.7) years. In women, GPER1 molecular variants had the most consistent associations with AD traits. GPER1 DNA methylation was associated with cognitive decline, tau tangle density, and global AD pathology score. GPER1 RNA expression in DLPFC was related to cognitive decline and tau tangle density. Other associations included associations of ER2 and ER1 sequence variants and DNA methylation with cognition. RNA expressions in DLPFC of genes involved in signaling mechanisms of activated ERs were also associated with cognitive decline and tau tangle density in women. In men (N = 651, average age at baseline: 77.4 [SD = 7.3]), there were less robust associations between ER molecular genomic variants and AD cognitive and pathologic traits. No consistent association was seen between ER molecular genomic variations and non-AD pathologies in either of the sexes.ER DNA methylation and RNA expression, and to some extent ER polymorphisms, were associated with AD cognitive and pathologic traits in women, and to a lesser extent in men. 

Estrogen Receptor Genes, Cognitive Decline, and Alzheimer Disease

Alzheimer's disease (AD), the most common type of dementia, is a neurodegenerative disorder characterized by progressive cognitive dysfunction. Epidemiological investigation has demonstrated that, after cardiovascular and cerebrovascular diseases, tumors, and other causes, AD has become a major health issue affecting elderly individuals, with its mortality rate acutely increasing each year. Regulatory cell death is the active and orderly death of genetically determined cells, which is ubiquitous in the development of living organisms and is crucial to the regulation of life homeostasis. With extensive research on regulatory cell death in AD, increasing evidence has revealed that ferroptosis, pyroptosis, and cuproptosis are closely related to the occurrence, development, and prognosis of AD. This paper will review the molecular mechanisms of ferroptosis, pyroptosis, and cuproptosis and their regulatory roles in AD to explore potential therapeutic targets for the treatment of AD.

Ferroptosis, Pyroptosis, and Cuproptosis in Alzheimer's Disease.

Furin is an important mammalian proprotein convertase that catalyzes the proteolytic maturation of a variety of prohormones and proproteins in the secretory pathway. In the brain, the substrates of furin include the proproteins of growth factors, receptors and enzymes. Emerging evidence, such as reduced FURIN mRNA expression in the brains of Alzheimer's disease patients or schizophrenia patients, has implicated a crucial role of furin in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Currently, compared to cancer and infectious diseases, the aberrant expression of furin and its pharmaceutical potentials in neurological diseases remain poorly understood. In this article, we provide an overview on the physiological roles of furin and its substrates in the brain, summarize the deregulation of furin expression and its effects in neurodegenerative and neuropsychiatric disorders, and discuss the implications and current approaches that target furin for therapeutic interventions. This review may expedite future studies to clarify the molecular mechanisms of furin deregulation and involvement in the pathogenesis of neurodegenerative and neuropsychiatric diseases, and to develop new diagnosis and treatment strategies for these diseases. 

/pdf/the-emerging-role-of-furin-in-neurodegenerative-and-35hrc2mx.pdf

The emerging role of furin in neurodegenerative and neuropsychiatric diseases

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The emerging role of furin in neurodegenerative and neuropsychiatric diseases