History and progress of hypotheses and clinical trials for Alzheimer’s disease

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Aug. 23, 2019

Abstract Alzheimer’s disease (AD) is a neurodegenerative characterized by progressive memory loss along with neuropsychiatric symptoms and decline in activities of daily life. Its main pathological features are cerebral atrophy, amyloid plaques, neurofibrillary tangles the brains patients. There various descriptive hypotheses regarding causes AD, including cholinergic hypothesis, tau propagation mitochondrial cascade calcium homeostasis neurovascular inflammatory metal ion lymphatic system hypothesis. However, ultimate etiology AD remains obscure. In this review, we discuss related clinical trials. Wealthy puzzles lessons have made it possible to develop explanatory theories identify potential strategies for therapeutic interventions AD. The combination hypometabolism autophagy deficiency likely be causative factor We further propose that fluoxetine, selective serotonin reuptake inhibitor, has treat

Language: Английский

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Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

Journal of Molecular Biology, Journal Year: 2019, Volume and Issue: 431(9), P. 1843 - 1868

Published: Jan. 18, 2019

Language: Английский

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Copper Dyshomeostasis in Neurodegenerative Diseases—Therapeutic Implications

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(23), P. 9259 - 9259

Published: Dec. 4, 2020

Copper is one of the most abundant basic transition metals in human body. It takes part oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining integrity blood vessels, as well iron homeostasis, antioxidant defense, neurotransmitter synthesis. may also be involved cell signaling participate modulation membrane receptor-ligand interactions, control kinase related phosphatase functions, many cellular pathways. Its role important controlling gene expression nucleus. In nervous system particular, copper myelination, by modulating synaptic activity excitotoxic death cascades induced neurotrophic factors, for various neuronal functions. Current data suggest that both excess levels deficiency can harmful, careful homeostatic important. This knowledge opens up an new area potential therapeutic interventions based on supplementation or removal neurodegenerative diseases including Wilson’s disease (WD), Menkes (MD), Alzheimer’s (AD), Parkinson’s (PD), others. However, much remains to discovered, how regulate homeostasis prevent neurodegeneration, when chelate copper, supplement it.

Language: Английский

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Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 13

Published: Jan. 29, 2020

Iron is an essential transition metal for numerous biologic processes in mammals. metabolism and homeostasis are regulated via several coordination mechanisms including absorption, utilization, recycling, storage.Iron dyshomeostasis can result intracellular excessive iron accumulation,thereby damaging cells, tissues organs through free oxygen radicals generation. Numerous studies have showed that overload of brain involved the pathological mechanism Alzheimer's disease.However,the underlying not been fully elucidated. Ferroptosis , a newly defined iron-dependent form cell death, which distinct from apoptosis, necrosis, autophagy other forms death,may provide us new viewpoints. Here, we summarizes current knowledge ferroptosis, reviews contributions ferroptosis disease.

Language: Английский

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Molecular mechanisms of ferroptosis and their involvement in brain diseases

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 244, P. 108373 - 108373

Published: March 8, 2023

Ferroptosis is a type of regulated cell death characterized by intracellular accumulation iron and reactive oxygen species, inhibition system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation lipid peroxidation. Since its discovery characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, involvement disease pathways. inducers include erastin, sorafenib, sulfasalazine glutamate, which, inhibiting prevent import cysteine into cells. RSL3, statins, Ml162 Ml210 induce ferroptosis peroxidase 4 (GPX4), which responsible for preventing formation peroxides, FIN56 withaferin trigger GPX4 degradation. On other side, inhibitors ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 BH4, interrupt peroxidation cascade. Additionally, deferoxamine, deferiprone N-acetylcysteine, targeting cellular pathways, also classified as inhibitors. Increased evidence has established distinct brain diseases, including Alzheimer's, Parkinson's Huntington's amyotrophic lateral sclerosis, multiple Friedreich's ataxia. Thus, deep understanding how contributes these it can be modulated, open new window opportunities novel therapeutic strategies targets. Other studies shown sensitivity cancer cells with mutated RAS induction that chemotherapeutic agents synergize tumor treatment. tempting consider may arise target mechanistic pathway treatment tumors. Therefore, this work provides an up-to-date review on molecular mechanisms their diseases. In addition, information main targets provided.

Language: Английский

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Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

Frontiers in Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: Dec. 11, 2019

Cellular growth, function and protection require proper iron management, ferritin plays a physiologically crucial role as the major sequestration storage protein. Ferritin is 24 subunit spherical shell protein composed of both light (FTL) heavy chain (FTH1) subunits, possessing complimentary iron-handling functions forming pores 3-fold 4-fold symmetry. Iron uptake through well-defined, but unloading process somewhat less generally focuses on lysosomal degradation although it may have an additional, energetically efficient pore mechanism. Hereditary Ferritinopathy (HF) or neuroferritinopathy autosomal dominant neurodegenerative disease caused by mutations in FTL C-terminal sequence, which turn cause disorder unraveling at allowing leakage enhanced formation toxic, improperly coordinated (ICI). Histopathologically, HF characterized deposition inclusion bodies (IBs) cells overexpress attempt to address accumulation while lacking ability clear its aggregates. Overexpression IB tax materially energetically, i.e., their synthesis disposal systems, hinder cellular transport other spatially dependent functions. ICI causes damage proteins lipids reactive oxygen species (ROS) because high levels brain oxygen, reductants general metabolism, taxing repair. can aggregation indirectly ROS-induced modification destabilization, more directly with mutant bridging. release are also linked misfunction ferritinophagy, sufficient initiate unique programmed cell death ferroptosis causing ROS lipid peroxidation. But buildup suggests suppressed elevated from together leading long-term ferroptotic-like state HF. Several these processes parallels line mouse models. This review addresses roles structure within above-mentioned framework, they relate associated disorders abnormal accumulation, aggregation, oxidative damage, resulting contributions cumulative stress death.

Language: Английский

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The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Sept. 1, 2022

Currently, there is no disease-modifying treatment available for Alzheimer's and Parkinson's disease (AD PD) that includes the highly controversial approval of Aβ-targeting antibody aducanumab AD. Hence, still an unmet need a neuroprotective drug in both AD PD. Type 2 diabetes risk factor Glucagon-like peptide 1 (GLP-1) hormone growth has shown effects preclinical studies, success GLP-1 mimetics phase II clinical trials PD raised new hope. are currently on market as treatments type diabetes. analogs safe, well tolerated, resistant to desensitization characterized clinic. Herein, we review existing evidence illustrate pathways induced following GLP-1R activation neurons, microglia astrocytes. The latter include synaptic protection, improvements cognition, learning motor function, amyloid pathology-ameliorating properties (Aβ, Tau, α-synuclein), suppression Ca

Language: Английский

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Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

Brain Sciences, Journal Year: 2021, Volume and Issue: 11(2), P. 215 - 215

Published: Feb. 10, 2021

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative characterized by decline in cognition. Over the last two decades, there has been significant growth investigation of cerebrospinal fluid (CSF) biomarkers for disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to efficacy existing core CSF such as total tau, phosphorylated amyloid-β (Aβ42), which diagnose early dementia stages disorder. The heterogeneity pathophysiology late-onset warrants biomarker toolbox; more showing other aspects mechanism are needed. focuses on new track pathology, those assess neuronal injury (VILIP-1 neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, MCP-1), synaptic dysfunction (SNAP-25 GAP-43), vascular dysregulation (hFABP), well α-synuclein levels TDP-43 pathology. Some these promising candidates they specific predict future rates cognitive decline. Findings combinations subclasses improve their diagnostic detecting associated pathological changes also presented.

Language: Английский

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Epigallocatechin-3-Gallate (EGCG): New Therapeutic Perspectives for Neuroprotection, Aging, and Neuroinflammation for the Modern Age

Biomolecules, Journal Year: 2022, Volume and Issue: 12(3), P. 371 - 371

Published: Feb. 25, 2022

Alzheimer’s and Parkinson’s diseases are the two most common forms of neurodegenerative diseases. The exact etiology these disorders is not well known; however, environmental, molecular, genetic influences play a major role in pathogenesis Using disease (AD) as archetype, pathological findings include aggregation Amyloid Beta (Aβ) peptides, mitochondrial dysfunction, synaptic degradation caused by inflammation, elevated reactive oxygen species (ROS), cerebrovascular dysregulation. This review highlights neuroinflammatory neuroprotective epigallocatechin-3-gallate (EGCG): medicinal component green tea, known nutraceutical that has shown promise modulating AD progression due to its antioxidant, anti-inflammatory, anti-aging abilities. report also re-examines current literature provides innovative approaches for EGCG be used preventive measure alleviate other disorders.

Language: Английский

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Autophagy mediates an amplification loop during ferroptosis

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(7)

Published: July 25, 2023

Ferroptosis, a programmed cell death, has been identified and associated with cancer various other diseases. Ferroptosis is defined as reactive oxygen species (ROS)-dependent death related to iron accumulation lipid peroxidation, which different from apoptosis, necrosis, autophagy, forms of death. However, accumulating evidence revealed link between autophagy ferroptosis at the molecular level suggested that involved in regulating iron-dependent peroxidation ROS during ferroptosis. Understanding roles pathophysiological processes may provide effective strategies for treatment ferroptosis-related In this review, we summarize current knowledge regarding regulatory mechanisms underlying ferroptosis, including metabolism, its association pathway. addition, discuss contribution elucidate role enhancer ROS-dependent

Language: Английский

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