The Role of Iron Metabolism, Lipid Metabolism, and Redox Homeostasis in Alzheimer’s Disease: from the Perspective of Ferroptosis

Wu, Lin-Yu; Xian, Xiaohui; Tan, Zixuan; Dong, Fang; Xu, Guangyu; Zhang, Min; Zhang, Feng

doi:10.1007/s12035-023-03245-7

Cited by 14 publications

(5 citation statements)

References 233 publications

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“…In addition to the best-characterized histological features of AD, such as the extracellular deposition of senile plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) made up of hyperphosphorylation of Tau, great attention has recently shifted to the roles of iron metabolism, lipid peroxidation, and oxidative stress in AD pathogenesis . Growing evidence indicates that iron imbalance can exacerbate toxic Aβ deposition and Tau hyperphosphorylation/aggregation and many studies link iron dyshomeostasis with the pathophysiology of AD; in particular, regional iron load appears to be a risk factor for more rapid cognitive decline …”

Section: Resultsmentioning

confidence: 99%

“…50 Growing evidence indicates that iron imbal- ance can exacerbate toxic Aβ deposition and Tau hyperphosphorylation/aggregation and many studies link iron dyshomeostasis with the pathophysiology of AD; in particular, regional iron load appears to be a risk factor for more rapid cognitive decline. 51 For the evaluation of neuroprotective properties, compounds 4g and 4d were selected for cellular assays. The first is because it exhibited the best inhibitory activity of ChEs in combination with the ability to modulate CB2R; the second is because it had binding affinity to CB2R but little or no antiChE activity.…”

Section: ■ Introductionmentioning

confidence: 99%

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Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo

Mugnaini,

Brizzi,

Paolino

et al. 2024

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is a neurodegenerative form of dementia characterized by the loss of synapses and a progressive decline in cognitive abilities. Among current treatments for AD, acetylcholinesterase (AChE) inhibitors have efficacy limited to symptom relief, with significant side effects and poor compliance. Pharmacological agents that modulate the activity of type-2 cannabinoid receptors (CB2R) of the endocannabinoid system by activating or blocking them have also been shown to be effective against neuroinflammation. Herein, we describe the design, synthesis, and pharmacological effects in vitro and in vivo of dual-acting compounds that inhibit AChE and butyrylcholinesterase (BChE) and target CB2R. Within the investigated series, compound 4g proved to be the most promising. It achieved IC 50 values in the low micromolar to submicromolar range against both human cholinesterase isoforms while antagonizing CB2R with K i of 31 nM. Interestingly, 4g showed neuroprotective effects on the SH-SY5Y cell line thanks to its ability to prevent oxidative stress-induced cell toxicity and reverse scopolamine-induced amnesia in the Y-maze forced alternation test in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo

Mugnaini,

Brizzi,

Paolino

et al. 2024

ACS Chem. Neurosci.

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“…The correlation between iron and osteoporosis has garnered increased attention as studies have revealed that disturbances in iron metabolism, such as iron overload and iron deficiency, may result in osteoporosis [51]. The equilibrium and soundness of bone tissue are regulated by preserving a balance between osteoclastic and osteogenic activities, with the remodeling process of bone tissue being a perpetual cycle.…”

Section: Ferroptosis With Osteoclasts and Osteoblastsmentioning

confidence: 99%

Ferroptosis: A Frontier in Osteoporosis

Maheshwari,

Singh,

Verma

2024

Horm Metab Res

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Reduced bone mass and degeneration of the microarchitecture of bone tissue are the hallmarks of osteoporosis, a bone metabolic disease that increases skeletal fragility and fracture susceptibility. Osteoporosis is primarily caused by unbalanced bone remodeling, in which bone synthesis is outpaced by bone resorption caused by osteoclasts. Along with the bone-building vitamins calcium and vitamin D, typical medications for treating osteoporosis include bisphosphonates and calcitonin. The present therapies effectively stop osteoclast activation that is too high, however they come with varying degrees of negative effects. Numerous factors can contribute to osteoporosis, which is characterized by a loss of bone mass and density due to the deterioration of the bone’s microstructure, which makes the bone more fragile. As a result, it is a systemic bone condition that makes patients more likely to fracture. Interest in the function of ferroptosis in the pathophysiology of osteoporosis is developing. In this review, we go through the shape of the cell, the fundamental mechanisms of ferroptosis, the relationship between osteoclasts and osteoblasts, the association between ferroptosis and diabetic osteoporosis, steroid-induced osteoporosis, and the relationship between ferroptosis and postmenopausal osteoporosis. The functions of ferroptosis and osteoporosis in cellular function, signaling cascades, pharmacological inhibition, and gene silencing have been better understood thanks to recent advances in biomedical research.

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“…Biochemical and transcriptomic analyses of mediators of iron metabolism, antioxidant defenses, oxidative stress, and lipid peroxidation in experimental disease models, autopsy material, and induced pluripotent stem cell (iPSCs) derived from patients indicate that ferroptosis is a major mechanism of cell death in a wide range of neurologic disorders. These include Alzheimer disease (AD), 64,72,76-82 Parkinson disease (PD), 55,83-87 amyotrophic lateral sclerosis (ALS), 88-92 Huntington disease, 93-95 Friedreich ataxia, 96-98 multiple sclerosis, 99-101 ischemic stroke, 47,102-105 intracerebral hemorrhage, 106,107 traumatic brain injury, 108 spinal cord injury, 109,110 epilepsy, 111-113 and glioma, 114 among others. This topic has been extensively reviewed, 16-21,115,116 and only few concepts will be emphasized in this study.…”

Section: Role Of Ferroptosis In Neurologic Diseasementioning

confidence: 99%

What Is the Role of Ferroptosis in Neurodegeneration?

Benarroch

2023

Neurology

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Ferroptosis is a unique form of programmed cell death pathway that is mechanistically different from necrosis, apoptosis, or autophagy.1 Ferroptosis is induced by reactive oxygen species (ROS) originating from multiple sources, especially accumulation of free intracellular divalent iron (Fe2+), leading to peroxidation of polyunsaturated fatty acids (PUFAs) and resulting in membrane damage (Figure). One major trigger of ferroptosis is decreased availability of intracellular antioxidant enzymes, particularly glutathione peroxidases (GPXs).1-7 Because of its high lipid concentration and oxygen consumption rate, the nervous tissue is extremely vulnerable to oxidative damage and ferroptosis. With aging, iron accumulates in the brain, which predisposes to and exacerbates these processes.8 Iron promotes ferroptosis both directly and as a cofactor required for the activity of enzymes mediating redox reactions and lipid peroxidation.9,10 Epigenetic regulation can determine cell sensitivity to ferroptosis by affecting intracellular iron levels, oxidative stress, and lipid metabolism.11 Ferroptosis affects all cell types in the nervous system, including neurons, glial cells, and pericytes.12 Microglia are the primary iron-accumulating cells in disease.13,14 Recent evidence indicates that iron-laden microglia have a critical role in ferroptosis associated with neurodegeneration.15 Studies in vitro, in experimental disease models, and in human brain tissue indicate that iron accumulation, oxidative stress, and lipid peroxidation are major disease mechanisms in a wide range of neurologic disorders. These studies also suggest that the different components of the ferroptosis pathway are potential targets for therapeutic intervention. The mechanisms of ferroptosis and its role in neurologic disorders have been the subject of several recent comprehensive reviews.7,8,16-21 Some of these concepts pertinent to neurodegeneration will be emphasized in this study.

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The Role of Iron Metabolism, Lipid Metabolism, and Redox Homeostasis in Alzheimer’s Disease: from the Perspective of Ferroptosis

Cited by 14 publications

References 233 publications

Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo

Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo

Ferroptosis: A Frontier in Osteoporosis

What Is the Role of Ferroptosis in Neurodegeneration?

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