Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Translational Neurodegeneration, Journal Year: 2022, Volume and Issue: 11(1)

Published: Jan. 25, 2022

Abstract Glutamate is the most commonly engaged neurotransmitter in mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic has also been implicated some neurodegenerative disease models, role apoptotic remains controversial setting chronic neurodegeneration. Nevertheless, it clear that synaptic dysregulation contributes neurodegeneration, evidenced by protective effects partial N -methyl- D -aspartate receptor antagonists. Here, we review evidence for sublethal relation neurodegeneration associated with Parkinson’s disease, Alzheimer’s amyotrophic lateral sclerosis Huntington’s disease. In contrast classic emerging implicates mitochondrial calcium handling post-synaptic We discuss mechanisms regulate uptake release, impact LRRK2, PINK1, Parkin, beta-amyloid glucocerebrosidase on transporters, autophagic loss axodendritic shrinkage. Finally, strategies normalizing flux into out matrix, thereby preventing toxicity dendritic loss. underlie increased or decreased release vary different model systems, a common set normalize can prevent may be neuroprotective multiple contexts.

Language: Английский

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Major depressive disorder: hypothesis, mechanism, prevention and treatment

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 9, 2024

Abstract Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, pathological mechanisms MDD underlying effects pharmacological treatments for are complex unclear, additional diagnostic therapeutic strategies still needed. The currently widely accepted theories pathogenesis include neurotransmitter receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis cytokine neuroplasticity hypothesis systemic influence but these cannot completely explain mechanism MDD. Even it hard to adopt only one reveal MDD, thus recent years, great progress has been made elucidating roles multiple organ interactions identifying novel approaches multitarget modulatory strategies, further revealing disease features Furthermore, some newly discovered potential targets studied antidepressants have attracted widespread attention, reagents even approved clinical treatment methods such as phototherapy acupuncture effective improvement symptoms. In this work, we comprehensively summarize latest research on diagnosis preventive medicines, well related trials.

Language: Английский

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Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 24(1), P. 23 - 39

Published: Oct. 31, 2022

Language: Английский

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The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: July 13, 2021

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, enhanced inflammation. These are associated cognitive decline neurobehavioral deficits. Although not a disease, it significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, general susceptibility. Conversely, life events related to mental stress trauma can also lead accelerated age-associated disorders dementia. Here, we review human mice rats, those modeling neurodegenerative diseases, that helped elucidate (1) dynamics mechanisms underlying biological pathological of main projecting systems brain (glutamatergic, cholinergic, dopaminergic) (2) effect defective glutamatergic, dopaminergic projection disabilities disorders, Alzheimer’s Parkinson’s diseases. Detailed knowledge age-related diseases be an element development effective ways treatment. In this context, briefly analyze which adverse glutaminergic could targeted by therapeutic strategies developed result our better understanding these damaging mechanisms.

Language: Английский

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The synapse as a treatment avenue for Alzheimer’s Disease

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 27(7), P. 2940 - 2949

Published: April 20, 2022

Language: Английский

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Advances in understanding the function of alpha-synuclein: implications for Parkinson’s disease

Brain, Journal Year: 2023, Volume and Issue: 146(9), P. 3587 - 3597

Published: May 15, 2023

The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years identifying disease-modifying therapies for that target alpha-synuclein. However, these treatments have not yet shown clear efficacy slowing the progression this disease. Several explanations exist issue. pathogenesis is complex and fully clarified heterogeneity disease, with diverse genetic susceptibility risk factors different clinical courses, adds further complexity. Thus, deep understanding physiological pathophysiological functions crucial. In review, we first describe cellular animal models developed to study pathological roles protein, including transgenic techniques, use viral vectors intracerebral injections fibrils. We then provide evidence tools are crucial modelling pathogenesis, causing protein misfolding aggregation, synaptic dysfunction, brain plasticity impairment cell-to-cell spreading species. particular, focus on possibility dissecting pre- postsynaptic effects both conditions. Finally, show how vulnerability specific neuronal cell types may facilitate systemic dysfunctions leading multiple network alterations. These functional alterations underlie motor non-motor manifestations occur before overt neurodegeneration. now understand therapeutic targeting patients requires caution, since exerts important functions. Moreover, interactions other molecules induce synergistic detrimental effects. only might be enough. Combined should considered future.

Language: 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, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 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.

Language: Английский

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The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 14, 2025

Abstract The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role different brain regions such as substantia nigra (SN) largely unexplored. In this study, we characterize tPA expression, activity, localization SN using a combination of retrograde tracing β-galactosidase reporter mice. We further investigate tPA’s potential pathology an α-synuclein mouse model Parkinson’s disease (PD). To mechanism action α-synuclein-mediated to identify possible therapeutic pathways, performed RNA-seq analysis used multiple transgenic models. These included deficient mice two newly developed mice, knock-in expressing endogenous levels proteolytically inactive (tPA Ala-KI) second overexpressing Ala-BAC). Our findings show that striatal GABAergic neurons send + projections dopaminergic (DA)-neurons released from SN-derived synaptosomes upon stimulation. also found increased following overexpression. Importantly, deficiency protects DA-neurons degeneration, prevents behavioral deficits, reduces microglia activation T-cell infiltration induced by indicates required for upregulation genes involved innate adaptive immune responses Overexpression Ala-KI only tPA, confirms tPA-mediated neuroinflammation neurodegeneration independent proteolytic activity. Moreover, overexpression Ala-BAC leads compared normal suggesting dose response. Finally, treatment with glunomab, neutralizing antibody selectively blocks binding N-methyl-D-aspartate receptor-1 (NMDAR1) without affecting NMDAR1 ion channel function, identifies interaction necessary response neurotoxicity. Thus, our data novel pathway promotes DA-neuron degeneration suggests intervention PD targeting tPA-NMDAR1 interaction.

Language: Английский

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Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders

Cells, Journal Year: 2022, Volume and Issue: 11(7), P. 1139 - 1139

Published: March 28, 2022

Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is predominant excitatory neurotransmitter where the astrocytes play pivotal role in maintaining extracellular levels through release uptake mechanisms. Astrocytes modulate calcium-mediated excitability several neurotransmitters neuromodulators, including glutamate, significantly neurotransmission. Accumulating evidence supports concept of excitotoxicity caused by astrocytic pathological conditions. Thus, current review highlights different vesicular non-vesicular mechanisms glutamate their implication diseases. As presynaptic neurons, also primarily meditated exocytosis. V-ATPase crucial acidification maintenance gradient that facilitates storage glutamate. Along with these, other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors so forth, contribute to under physiological Events hampered could promote inflamed trigger repetitive This be favorable towards development worsening Therefore, across diseases, we relations between defective signaling events homeostasis. The optimum regulation transmission pave way for management these diseases add therapeutic value.

Language: Английский

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Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12928 - 12928

Published: Oct. 26, 2022

Parkinson’s disease (PD) is a multisystem alpha-synucleinopathic neurodegenerative and the most prevalent disorder after Alzheimer’s with high incidence rate in elderly population. PD highly multifactorial etiology has complex wide-ranging pathogenic mechanisms. Environmental exposures genetic predisposition are prominent risk factors. However, current evidence suggests that an intimate link may exist between factor of sleep disturbance pathogenesis. characterized by pathological hallmarks alpha-synuclein aggregations dopaminergic neuron degeneration substantia nigra. The loss dopamine-producing neurons results both motor non-motor symptoms, commonly, bradykinesia, tremor, rigidity, psychiatric disorders, disorders gastrointestinal problems. Factors exacerbate accumulation dopamine include neuroinflammation glymphatic system impairment. Extracellular can induce inflammatory response which lead to neural cell death inhibition neurogenesis. functions optimally remove extracellular brain solutes during therefore disruption be crucial progression as well factor. This literature review interprets analyses data from experimental epidemiological studies determine recent advances establishing relationship dysfunction, disturbance, pathogenesis progression. addresses limitations surrounding ability affirm causal improved clearance increased quality prevention management. Furthermore, this proposes potential therapeutic approaches could utilize protective mechanism sleep, promote reduce symptom severity patients.

Language: Английский

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