Hallmarks of neurodegenerative diseases

Cell, Journal Year: 2023, Volume and Issue: 186(4), P. 693 - 714

Published: Feb. 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.

Language: Английский

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Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 6, 2022

Abstract Ischemic stroke is caused primarily by an interruption in cerebral blood flow, which induces severe neural injuries, and one of the leading causes death disability worldwide. Thus, it great necessity to further detailly elucidate mechanisms ischemic find out new therapies against disease. In recent years, efforts have been made understand pathophysiology stroke, including cellular excitotoxicity, oxidative stress, cell processes, neuroinflammation. meantime, a plethora signaling pathways, either detrimental or neuroprotective, are also highly involved forementioned pathophysiology. These pathways closely intertwined form complex network. Also, these reveal therapeutic potential, as targeting could possibly serve approaches stroke. this review, we describe categorize them based on pathophysiological processes they participate in. Therapeutic associated with mentioned above, discussed. Meanwhile, clinical trials regarding potentially target involved, summarized details. Conclusively, review elucidated potential molecular related underlying summarize targeted various pathophysiology, particular reference future prospects for treating

Language: Английский

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Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(6), P. 688 - 701

Published: June 1, 2022

Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons five AD mouse models vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of pH, multiplex confocal imaging correlative light electron microscopy. Autolysosome acidification declines well before extracellular amyloid deposition, associated with lowered vATPase activity build-up Aβ/APP-βCTF selectively enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This pattern, termed PANTHOS (poisonous anthos (flower)), also present brains. Additional AVs coalesce peri-nuclear networks tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal permeabilization, cathepsin release lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual exhibiting are the principal source senile plaques precursor protein models.

Language: Английский

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The endotoxin hypothesis of neurodegeneration

Journal of Neuroinflammation, Journal Year: 2019, Volume and Issue: 16(1)

Published: Sept. 13, 2019

The endotoxin hypothesis of neurodegeneration is the that causes or contributes to neurodegeneration. Endotoxin a lipopolysaccharide (LPS), constituting much outer membrane gram-negative bacteria, present at high concentrations in gut, gums and skin other tissue during bacterial infection. Blood plasma levels are normally low, but elevated infections, gut inflammation, gum disease neurodegenerative disease. Adding such blood healthy humans induces systemic inflammation brain microglial activation. body rodents activation, priming and/or tolerance, memory deficits loss synapses neurons. promotes amyloid β tau aggregation neuropathology, suggesting possibility synergises with different aggregable proteins give diseases. Alzheimer's disease, which accelerated by including binds directly APOE, APOE4 variant both sensitises predisposes Intestinal permeability increases early Parkinson's injection into mice α-synuclein production aggregation, as well dopaminergic neurons substantia nigra. microbiome changes changing endotoxin-producing species can affect patients mouse models. amyotrophic lateral sclerosis, TDP-43 neuropathology. Peripheral diseases elevate endotoxin, sepsis, AIDS liver failure, also result indirectly activates microglia damage via nitric oxide, oxidants cytokines, phagocytosis unproven, if correct, then may be reduced decreasing endotoxin-induced neuroinflammation.

Language: Английский

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Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration

Frontiers in Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: July 10, 2018

Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms death. induced by disruption glutathione synthesis or inhibition peroxidase 4, exacerbated iron, prevented radical scavengers such as ferrostatin-1, liproxstatin-1 endogenous vitamin E. terminates with mitochondrial dysfunction toxic lipid peroxidation. Although conclusive identification ferroptosis in vivo challenging, several salient very well established features neurodegenerative diseases are consistent ferroptosis, including peroxidation, iron dysregulation. Accordingly, interest the role neurodegeneration escalating specific evidence rapidly emerging. One aspect that has thus far received little attention antioxidant transcription factor nuclear erythroid 2-related 2 (Nrf2). This regulates hundreds genes, which many either directly indirectly involved modulating metabolism glutathione, lipids, function. potentially positions Nrf2 key deterministic component onset outcomes ferroptotic stress. The minimal direct currently available this indicates may be critical for protection against ferroptosis. In contrast, abundant demonstrates enhancing signaling potently neuroprotective models neurodegeneration, although exact mechanism achieved unclear. Further studies required to determine extent effects activation involve prevention

Language: Английский

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From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

Computational and Structural Biotechnology Journal, Journal Year: 2021, Volume and Issue: 19, P. 4641 - 4657

Published: Jan. 1, 2021

Pyroptosis, apoptosis and necroptosis are the most genetically well-defined programmed cell death (PCD) pathways, they intricately involved in both homeostasis disease. Although identification of key initiators, effectors executioners each these three PCD pathways has historically delineated them as distinct, growing evidence highlighted extensive crosstalk among them. These observations have led to establishment concept PANoptosis, defined an inflammatory pathway regulated by PANoptosome complex with features pyroptosis, and/or that cannot be accounted for any alone. In this review, we provide a brief overview research history necroptosis. We then examine intricate discuss current PANoptosis. also detail molecular assembly complex, scaffold contemporaneous engagement molecules from apoptosis, PANoptosis is now known critically many diseases, including infection, sterile inflammation cancer, future discovery novel PANoptotic components will continue broaden our understanding fundamental processes inform development new therapeutics.

Language: Английский

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Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(10), P. 3082 - 3082

Published: Oct. 9, 2018

Neuronal cell death in the central nervous system has always been a challenging process to decipher. In normal physiological conditions, neuronal is restricted adult brain, even aged individuals. However, pathological conditions of various neurodegenerative diseases, and shrinkage specific region brain represent fundamental feature across different diseases. this review, we will briefly go through general pathways describe evidence for context individual common discussing our current understanding by connecting with renowned pathogenic proteins, including Tau, amyloid-beta, alpha-synuclein, huntingtin TDP-43.

Language: Английский

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How macrophages deal with death

Nature reviews. Immunology, Journal Year: 2019, Volume and Issue: 19(9), P. 539 - 549

Published: April 24, 2019

Language: Английский

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Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(22), P. 8765 - 8765

Published: Nov. 20, 2020

Ferroptosis is a type of cell death that was described less than decade ago. It caused by the excess free intracellular iron leads to lipid (hydro) peroxidation. Iron essential as redox metal in several physiological functions. The brain one organs known be affected homeostatic balance disruption. Since 1960s, increased concentration central nervous system has been associated with oxidative stress, oxidation proteins and lipids, death. Here, we review main mechanisms involved process ferroptosis such peroxidation, glutathione peroxidase 4 enzyme activity, metabolism. Moreover, association pathophysiology some neurodegenerative diseases, namely Alzheimer’s, Parkinson’s, Huntington’s also addressed.

Language: Английский

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Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Frontiers in Cellular Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: March 19, 2020

A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is prominent cause death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion ionic imbalance, followed by cell membrane depolarization, calcium (Ca2+) overload, extracellular accumulation excitatory amino acid glutamate. If tight physiological regulation fails clear surplus this neurotransmitter, subsequent prolonged activation glutamate receptors forms vicious circle between elevated concentrations intracellular Ca2+ ions aberrant release, aggravating effect pathway. The downstream Ca2+-dependent enzymes has catastrophic impact on nervous tissue leading death, accompanied formation free radicals, edema, inflammation. After decades "neuron-centric" approaches, recent research also finally shed some light role glial cells diseases. It becoming more evident that neurons glia depend each other. Neuronal cells, astrocytes, microglia, NG2 glia, oligodendrocytes all have their roles what However, who main contributor pathway, unsuspecting victim? In review article, we summarize so-far-revealed central system, with particular attention ischemia-induced excitotoxicity, its origins, consequences.

Language: Английский

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