The mechanisms of ferroptosis and its role in alzheimer’s disease

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Авг. 26, 2022

Alzheimer's disease (AD) accounts for two-thirds of all dementia cases, affecting 50 million people worldwide. Only four the more than 100 AD drugs developed thus far have successfully improved symptoms. Furthermore, these improvements are only temporary, as no treatment can stop or reverse progression. A growing number recent studies demonstrated that iron-dependent programmed cell death, known ferroptosis, contributes to AD-mediated nerve death. The ferroptosis pathways within cells include iron homeostasis regulation, cystine/glutamate (Glu) transporter (system xc-), glutathione (GSH)/glutathione peroxidase 4 (GPX4), and lipid peroxidation. In regulation pathway homeostasis, abnormal uptake, excretion storage in lead increased intracellular free Fenton reactions. decreased Glu expression leads accumulation outside cells, resulting inhibition system xc- pathway. GSH depletion causes abnormalities GPX4, leading excessive peroxides. Alterations specific amino acid metabolism eventually ferroptosis. This review explores connection between signaling metabolism, potentially informing future diagnosis methodologies.

Язык: Английский

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Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

Nutrients, Год журнала: 2022, Номер 14(5), С. 917 - 917

Опубликована: Фев. 22, 2022

The monoamine model of depression has long formed the basis drug development but fails to explain treatment resistance or associations with stress inflammation. Recent animal research, clinical trials ketamine (a glutamate receptor antagonist), neuroimaging and microbiome studies provide increasing evidence glutamatergic dysfunction in other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, brain injury forms rationale for this review. Glutamate is brain's principal excitatory neurotransmitter (NT), a metabolic synthesis substrate, an immune mediator. These overlapping roles multiple NT types complicate research into neurotransmission. microcircuit comprises neurons, astrocytes controlling synaptic space levels, through reuptake, inhibitory GABA interneurons. Astroglia generate respond inflammatory mediators. microcircuits also act at brain/body interface via microbiome, kynurenine pathway, hypothalamus-pituitary-adrenal axis. Disruption excitatory/inhibitory homeostasis causing neuro-excitotoxicity, neuronal impairment, causes cognition symptoms limbic prefrontal regions, respectively. Persistent reduces plasticity growth death tissue atrophy diseases. A conceptual overview activity peripheral interfacing presented, common mechanisms that diseases share when disrupted.

Язык: Английский

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Is L-Glutamate Toxic to Neurons and Thereby Contributes to Neuronal Loss and Neurodegeneration? A Systematic Review

Brain Sciences, Год журнала: 2022, Номер 12(5), С. 577 - 577

Опубликована: Апрель 29, 2022

L-glutamate (L-Glu) is a nonessential amino acid, but an extensively utilised excitatory neurotransmitter with critical roles in normal brain function. Aberrant accumulation of L-Glu has been linked to neurotoxicity and neurodegeneration. To investigate this further, we systematically reviewed the literature evaluate effects on neuronal viability pathogenesis and/or progression neurodegenerative diseases (NDDs). A search PubMed, Medline, Embase, Web Science Core Collection was conducted retrieve studies that investigated association between pathology for five NDDs: Alzheimer’s disease (AD), Parkinson’s (PD), multiple sclerosis (MS), amyotrophic lateral (ALS), Huntington’s (HD). Together, 4060 were identified, which 71 met eligibility criteria. Despite several inadequacies, including small sample size, employment supraphysiological concentrations, range administration routes, it concluded exposure vitro or vivo pathogenic mechanisms influence viability. These include oxidative stress, reduced antioxidant defence, neuroinflammation, altered levels, protein accumulations, excitotoxicity, mitochondrial dysfunction, intracellular calcium level changes, histology, cognitive function, animal behaviour. This implies clinical epidemiological are required assess potential harm arising from excessive intake exogenous L-Glu.

Язык: Английский

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Glial Glutamine Homeostasis in Health and Disease

Neurochemical Research, Год журнала: 2022, Номер 48(4), С. 1100 - 1128

Опубликована: Ноя. 2, 2022

Язык: Английский

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Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila

Nature Metabolism, Год журнала: 2023, Номер 5(11), С. 2002 - 2019

Опубликована: Ноя. 6, 2023

Abstract Glucose is the primary source of energy for brain; however, it remains controversial whether, upon neuronal activation, glucose primarily used by neurons ATP production or if partially oxidized in astrocytes, as proposed astrocyte–neuron lactate shuttle model glutamatergic neurons. Thus, an vivo picture metabolism during cognitive processes missing. Here, we uncover Drosophila melanogaster a glia-to-neuron alanine transfer involving aminotransferase that sustains memory formation. Following associative conditioning, glycolysis glial cells produces alanine, which back-converted into pyruvate cholinergic olfactory center to uphold their increased mitochondrial needs. Alanine, mediator glia–neuron coupling, could be alternative systems. In parallel, dedicated transporter imports specifically long-term memory, directly transferring use pentose phosphate pathway. Our results demonstrate compartmentalization between and

Язык: Английский

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Astrocytes regulate inhibitory neurotransmission through GABA uptake, metabolism, and recycling

Essays in Biochemistry, Год журнала: 2023, Номер 67(1), С. 77 - 91

Опубликована: Фев. 21, 2023

Abstract Synaptic regulation of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) is essential for brain function. Cerebral GABA homeostasis tightly regulated through multiple mechanisms and directly coupled to metabolic collaboration between neurons astrocytes. In this essay, we outline discuss fundamental roles astrocytes in regulating synaptic signaling. A major fraction removed from synapse by astrocytic uptake. Astrocytes utilize as a substrate support glutamine synthesis. The astrocyte-derived subsequently transferred where it serves precursor neuronal flow collectively termed GABA-glutamine cycle sustain synthesis certain areas, are even capable synthesizing releasing modulate transmission. majority oxidative metabolism takes place astrocytes, which also leads GABA-related metabolite γ-hydroxybutyric (GHB). physiological endogenous GHB remain unclear, but may be related tonic inhibition plasticity. Disrupted signaling dysfunctional astrocyte handling implicated several diseases including epilepsy Alzheimer’s disease. under control uptake, metabolism, recycling therefore serve relevant targets ameliorate pathological

Язык: Английский

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Bioelectronic Medicine: a multidisciplinary roadmap from biophysics to precision therapies

Frontiers in Integrative Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Фев. 19, 2024

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation nervous system by precise delivery electrical current for treatment conditions, such post-stroke movement recovery or drug-resistant disorders. The unquestionable impact is underscored successful translation to humans in last decades, long list preclinical studies. Given emergency accelerating progress new neuromodulation treatments (i.e., hypertension, autoimmune degenerative diseases), collaboration between multiple fields imperative. This work intends foster multidisciplinary bring together different provide fundamental basis underlying Medicine. In this review we will go from biophysics cell membrane, which consider inner core neuromodulation, patient care. We discuss recently discovered mechanism neurotransmission switching how it design, update on neuronal glial health disease. advances biomedical technology have facilitated collection large amounts data, thereby introducing challenges data analysis. approaches high throughput analysis, encompassing big networks, artificial intelligence, internet things. Emphasis be placed understanding electrochemical properties neural interfaces, along with integration biocompatible reliable materials compliance regulations translational applications. Preclinical validation foundational process, critical aspects animal Finally, focus point-of-care ultimate goal bioelectronic medicine. a call scientists common endeavor: accelerate decoding era therapeutic possibilities.

Язык: Английский

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Metabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer’s disease

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 7, 2024

The metabolic implications in Alzheimer's disease (AD) remain poorly understood. Here, we conducted a metabolomics study on moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, brain amyloid-β deposition 421). These demonstrated synergistic performances across stages subpopulations enhanced the differentiation of AD beyond demographics Apolipoprotein E ε4 allele (APOE-ε4). We validated their eight data sets (total n 7685) obtained from Disease Neuroimaging Initiative (ADNI) Religious Orders Study Memory Aging Project (ROSMAP). Importantly, identified are linked to blood ammonia homeostasis. further confirmed elevated level through development 1060). Our findings highlight as emphasize metabolite-mediated disturbance its potential signature therapeutic target for AD.

Язык: Английский

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Essential Role of Astrocytes in Learning and Memory

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(3), С. 1899 - 1899

Опубликована: Фев. 5, 2024

One of the most biologically relevant functions astrocytes within CNS is regulation synaptic transmission, i.e., physiological basis for information transmission between neurons. Changes in strength connections are indeed thought to be cellular learning and memory. Importantly, have been demonstrated tightly regulate these processes via release several gliotransmitters linked astrocytic calcium activity as well astrocyte–neuron metabolic coupling. Therefore, seem integrators actors upon learning- memory-relevant information. In this review, we focus on role memory processes. We delineate recognized inputs outputs explore influence manipulating behaviour across diverse paradigms. conclude that various manners. Appropriate Ca2+ dynamics being increasingly identified central contributors formation retrieval. addition, brain rhythms essential cognition, cooperation required consolidation.

Язык: Английский

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L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review

Nutrients, Год журнала: 2024, Номер 16(8), С. 1232 - 1232

Опубликована: Апрель 20, 2024

L-carnitine (LC), a vital nutritional supplement, plays crucial role in myocardial health and exhibits significant cardioprotective effects. LC, being the principal constituent of clinical-grade supplements, finds extensive application recovery treatment diverse cardiovascular cerebrovascular disorders. However, controversies persist regarding utilization LC nervous system diseases, with varying effects observed across numerous mental neurological This article primarily aims to gather analyze database information comprehensively summarize therapeutic potential patients suffering from diseases while providing valuable references for further research.

Язык: Английский

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