Hallmarks of neurodegenerative diseases

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

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Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Язык: Английский

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Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets

Cells, Год журнала: 2024, Номер 13(5), С. 423 - 423

Опубликована: Фев. 28, 2024

The involvement of central and peripheral inflammation in the pathogenesis prognosis major depressive disorder (MDD) has been demonstrated. increase pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-18, TNF-α) individuals with depression may elicit neuroinflammatory processes inflammation, mechanisms that, turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation dysbiosis induce alterations tryptophan metabolism, culminating decreased serotonin synthesis, impairments neuroplasticity-related mechanisms, glutamate-mediated excitotoxicity. This review aims highlight inflammatory (neuroinflammation, dysbiosis) involved pathophysiology MDD explore novel anti-inflammatory therapeutic approaches for this psychiatric disturbance. Several lines evidence have indicated that addition antidepressants, physical exercise, probiotics, nutraceuticals (agmatine, ascorbic acid, vitamin D) possess effects their antidepressant properties. Further studies are necessary benefits these alternative therapies MDD.

Язык: Английский

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Inflammation: A New Look at an Old Problem

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(9), С. 4596 - 4596

Опубликована: Апрель 21, 2022

Pro-inflammatory stress is inherent in any cells that are subject to damage or threat of damage. It defined by a number universal components, including oxidative stress, cellular response DNA damage, unfolded protein mitochondrial and endoplasmic reticulum changes autophagy, inflammasome formation, non-coding RNA response, formation an inducible network signaling pathways, epigenetic changes. The presence receptor secretory phenotype many the cause tissue pro-inflammatory stress. key phenomenon determining occurrence classical inflammatory focus microvascular (exudation, leukocyte migration alteration zone). This same reaction at systemic level leads development life-critical inflammation. From this standpoint, we can characterize common mechanisms pathologies differ their clinical appearance. division inflammation into alternative variants has deep evolutionary roots. Evolutionary aspects also described review. aim review provide theoretical arguments for need up-to-date theory relationship between human pathological processes based on integrative role molecular

Язык: Английский

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Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Июль 3, 2023

Abstract Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge basic research clinical practice. The similarities differences between stroke AD terms pathogenesis pathophysiology, however, have rarely been comparably reviewed. Here, we discuss background recent progresses that important informative related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity NMDAR-mediated Ca 2+ influx essential neuronal function cell survival. An ischemic insult, can cause rapid increases glutamate concentration excessive activation NMDARs, leading to swift overload cells acute excitotoxicity within hours days. On other hand, mild upregulation NMDAR activity, commonly seen animal models patients, is not immediately cytotoxic. Sustained hyperactivity dysregulation lasting from months years, nevertheless, be pathogenic slowly evolving events, i.e. degenerative excitotoxicity, development AD/ADRD. Specifically, mediated by extrasynaptic NMDARs (eNMDARs) downstream pathway transient potential cation channel subfamily M member (TRPM) primarily responsible excitotoxicity. subunit GluN3A plays “gatekeeper” role neuroprotective against both chronic Thus, share an NMDAR- -mediated mechanism provides common target preventive possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs was approved Federal Drug Administration (FDA) symptomatic treatment moderate-to-severe with variable efficacy. According eNMDARs, it conceivable MEM eNMDAR antagonists should administered much earlier, preferably during presymptomatic phases This anti-AD could simultaneously serve as preconditioning strategy attacks ≥ 50% patients. Future on regulation enduring control homeostasis, events will provide promising opportunity understand treat AD/ADRD stroke.

Язык: Английский

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Targeting synapse function and loss for treatment of neurodegenerative diseases

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 23(1), С. 23 - 42

Опубликована: Ноя. 27, 2023

Язык: Английский

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Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6521 - 6521

Опубликована: Июнь 13, 2024

Glutamate is the main excitatory neurotransmitter in brain wherein it controls cognitive functional domains and mood. Indeed, areas involved memory formation consolidation as well fear emotional processing, such hippocampus, prefrontal cortex, amygdala, are predominantly glutamatergic. To ensure physiological activity of brain, glutamatergic transmission finely tuned at synaptic sites. Disruption mechanisms responsible for glutamate homeostasis may result accumulation excessive levels, which turn leads to increased calcium mitochondrial abnormalities, oxidative stress, eventually cell atrophy death. This condition known glutamate-induced excitotoxicity considered a pathogenic mechanism several diseases central nervous system, including neurodevelopmental, substance abuse, psychiatric disorders. On other hand, these disorders share neuroplasticity impairments areas, accompanied by structural remodeling neurons. In current narrative review, we will summarize role both pathophysiology therapeutic interventions neurodevelopmental adult mental with focus on autism spectrum disorders, drugs under preclinical clinical development treatment different that dysfunctions. Although evidence still limited more studies required, regulation attracting attention potential crucial target control diseases.

Язык: Английский

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Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 5587 - 5587

Опубликована: Май 21, 2024

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies ALS, particularly sporadic ALS of unknown diverse etiologies, we must identify key, convergent mechanisms disease pathogenesis. This review focuses on origin effects glutamate-mediated excitotoxicity in (the cortical hyperexcitability hypothesis), which increased glutamatergic signaling causes neurons to become hyperexcitable eventually die. We characterize both primary secondary contributions excitotoxicity, referring processes taking place at synapse within cell, respectively. ‘Primary pathways’ include upregulation calcium-permeable AMPA receptors, dysfunction EAAT2 astrocytic glutamate transporter, release from presynaptic terminal, reduced inhibition by interneurons—all have been observed patients model systems. ‘Secondary changes mitochondrial morphology function, production reactive oxygen species, endoplasmic reticulum (ER) stress. By identifying key targets cascade, emphasize importance pathway pathogenesis suggest that intervening could be developing disease.

Язык: Английский

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Targeting Mitochondrial Dysfunction in Cerebral Ischemia: Advances in Pharmacological Interventions

Antioxidants, Год журнала: 2025, Номер 14(1), С. 108 - 108

Опубликована: Янв. 18, 2025

The study of mitochondrial dysfunction has become increasingly pivotal in elucidating the pathophysiology various cerebral pathologies, particularly neurodegenerative disorders. Mitochondria are essential for cellular energy metabolism, regulation reactive oxygen species (ROS), calcium homeostasis, and execution apoptotic processes. Disruptions function, driven by factors such as oxidative stress, excitotoxicity, altered ion balance, lead to neuronal death contribute cognitive impairments several brain diseases. Mitochondrial can arise from genetic mutations, ischemic events, hypoxia, other environmental factors. This article highlights critical role progression diseases discusses need targeted therapeutic strategies attenuate damage, restore enhance neuroprotection.

Язык: Английский

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Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies

Functional & Integrative Genomics, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 23, 2025

Язык: Английский

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