Xinyue Deng, Wen Zheng, Yan Yang, Zhijian Yang, Huan Li, Zhi Song, Jiangang Wang, H. Deng, L. Yuan
Parkinson’s disease (PD) is a clinical syndrome and a heterogeneous group of neurodegenerative conditions with variable pathologies and clinical sub-entities, characterized by motor symptoms and non-motor features. PD represents an outcome of the combination of genes and other risk or protective factors. Patients with variants in the phospholipase A2 group VI gene (PLA2G6) can present complex Parkinsonian phenotypes. This study reported a PD patient with typical motor symptoms of PD, including bradykinesia, gait disturbance, rigidity, and rest tremor, who also suffered from nocturia, constipation, and sleeping problems. Two PLA2G6 variants, c.402C>T and c.2327_2328del, were identified in the patient by whole exome sequencing followed by Sanger sequencing. The transition c.402C>T was predicted to generate an alternative acceptor splice site, though the minigene splicing assay showed negative in vitro outcomes. The novel variant c.2327_2328del was predicted to result in a truncated protein. These two variants may be pathogenic in PD or increase the susceptibility to PD individually or collaboratively. This discovery may enrich the genetic landscape of PLA2G6-associated PD and confirm the notion of prioritizing whole exome sequencing analysis in patients with PD.
{"title":"Identification of PLA2G6 variants in a Chinese patient with Parkinson's disease","authors":"Xinyue Deng, Wen Zheng, Yan Yang, Zhijian Yang, Huan Li, Zhi Song, Jiangang Wang, H. Deng, L. Yuan","doi":"10.20517/and.2023.06","DOIUrl":"https://doi.org/10.20517/and.2023.06","url":null,"abstract":"Parkinson’s disease (PD) is a clinical syndrome and a heterogeneous group of neurodegenerative conditions with variable pathologies and clinical sub-entities, characterized by motor symptoms and non-motor features. PD represents an outcome of the combination of genes and other risk or protective factors. Patients with variants in the phospholipase A2 group VI gene (PLA2G6) can present complex Parkinsonian phenotypes. This study reported a PD patient with typical motor symptoms of PD, including bradykinesia, gait disturbance, rigidity, and rest tremor, who also suffered from nocturia, constipation, and sleeping problems. Two PLA2G6 variants, c.402C>T and c.2327_2328del, were identified in the patient by whole exome sequencing followed by Sanger sequencing. The transition c.402C>T was predicted to generate an alternative acceptor splice site, though the minigene splicing assay showed negative in vitro outcomes. The novel variant c.2327_2328del was predicted to result in a truncated protein. These two variants may be pathogenic in PD or increase the susceptibility to PD individually or collaboratively. This discovery may enrich the genetic landscape of PLA2G6-associated PD and confirm the notion of prioritizing whole exome sequencing analysis in patients with PD.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87246076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neurodegenerative disorders represent a group of aging-related diseases affecting the different parts of the central nervous system. Axonal degeneration is among the leading causes of morbidity and disease progression in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurogenerative disorders. The unique structures of axons may make them particularly vulnerable to internal homeostasis. The axonal endoplasmic reticulum (ER) has emerged as one of the most important hallmarks in those neurodegenerative disorders associated with dysfunction of axonal transport, lipid synthesis, calcium dynamics, and interactions with other organelles. In this review, we summarize the role of tubular ER and its resident proteins in axonal degeneration, which emerges as an early pathological event in the axonal degeneration process. We also discuss the potential relationship between autophagy and tubular ER. With this review, we can consolidate the recent research advances in the role of tubular ER in axonal degeneration associated with several major neurodegenerative disorders and improve our understanding of axon pathophysiology and potential target therapies.
{"title":"The role of the tubular endoplasmic reticulum in the axonal degeneration associated with neurodegenerative disorders","authors":"Panpan Wang, Murad Al-Nusaif, Weidong Le","doi":"10.20517/and.2023.12","DOIUrl":"https://doi.org/10.20517/and.2023.12","url":null,"abstract":"Neurodegenerative disorders represent a group of aging-related diseases affecting the different parts of the central nervous system. Axonal degeneration is among the leading causes of morbidity and disease progression in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurogenerative disorders. The unique structures of axons may make them particularly vulnerable to internal homeostasis. The axonal endoplasmic reticulum (ER) has emerged as one of the most important hallmarks in those neurodegenerative disorders associated with dysfunction of axonal transport, lipid synthesis, calcium dynamics, and interactions with other organelles. In this review, we summarize the role of tubular ER and its resident proteins in axonal degeneration, which emerges as an early pathological event in the axonal degeneration process. We also discuss the potential relationship between autophagy and tubular ER. With this review, we can consolidate the recent research advances in the role of tubular ER in axonal degeneration associated with several major neurodegenerative disorders and improve our understanding of axon pathophysiology and potential target therapies.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82546867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In Parkinson's disease (PD), the accumulation of misfolded α-synuclein (α-syn) in the brain is a major characteristic of the pathology. α-Syn formation and aggregation may originate in the enteric nervous system and pathologic α-syn can be transmitted to the central nervous system via the vagus nerve. In this commentary, we summarize the findings of Yang et al.[1] in which they report on the ability of a Parkinson’s disease patient's intestinal and vagus lysates containing pathologic α-syn to template endogenous rat α-syn culminating in the spread of pathologic α-syn, deposition of pathologic α-syn, and neuroinflammation in different brain regions and neurodegeneration of dopamine neurons. These observations are discussed with other studies supporting the significance of the gastrointestinal system in PD pathogenesis and future directions of research are highlighted.
{"title":"A new Perspective on Parkinson's disease: exploring the involvement of intestine and vagus lysates in α-synucleinopathy propagation","authors":"R. Ullah, V. Dawson, T. Dawson","doi":"10.20517/and.2023.07","DOIUrl":"https://doi.org/10.20517/and.2023.07","url":null,"abstract":"In Parkinson's disease (PD), the accumulation of misfolded α-synuclein (α-syn) in the brain is a major characteristic of the pathology. α-Syn formation and aggregation may originate in the enteric nervous system and pathologic α-syn can be transmitted to the central nervous system via the vagus nerve. In this commentary, we summarize the findings of Yang et al.[1] in which they report on the ability of a Parkinson’s disease patient's intestinal and vagus lysates containing pathologic α-syn to template endogenous rat α-syn culminating in the spread of pathologic α-syn, deposition of pathologic α-syn, and neuroinflammation in different brain regions and neurodegeneration of dopamine neurons. These observations are discussed with other studies supporting the significance of the gastrointestinal system in PD pathogenesis and future directions of research are highlighted.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74443996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parkinson’s disease (PD) is a common neurodegenerative disease, pathologically characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. Although various biomarkers and imaging criteria for PD have been established, objective and reliable evaluation methods are still lacking. Electroneurography, as an objective measurement of evoked compound muscle action potentials, is used to assess the integrity of the peripheral nerve and is important in the diagnosis and differential diagnosis of PD with neuromuscular injury. Moreover, it provides references for the evaluation and quantification of the motor function in PD. Here, we summarize recent advances in clinical research of electroneurography in PD, including the peripheral nerve conduction velocity, needle electromyography, surface electromyography, and motion unit number estimation. The potential values of electroneurography in PD diagnosis are also involved.
{"title":"Electroneurography abnormality in Parkinson’s disease: a potential biomarker to help diagnosis","authors":"Yiying Hu","doi":"10.20517/and.2022.04","DOIUrl":"https://doi.org/10.20517/and.2022.04","url":null,"abstract":"Parkinson’s disease (PD) is a common neurodegenerative disease, pathologically characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. Although various biomarkers and imaging criteria for PD have been established, objective and reliable evaluation methods are still lacking. Electroneurography, as an objective measurement of evoked compound muscle action potentials, is used to assess the integrity of the peripheral nerve and is important in the diagnosis and differential diagnosis of PD with neuromuscular injury. Moreover, it provides references for the evaluation and quantification of the motor function in PD. Here, we summarize recent advances in clinical research of electroneurography in PD, including the peripheral nerve conduction velocity, needle electromyography, surface electromyography, and motion unit number estimation. The potential values of electroneurography in PD diagnosis are also involved.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85218528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jia Yu, C. Sgobio, Xuan Yang, Yuehan Peng, X. Chen, Lixin Sun, Hoon Shim, H. Cai
Aim: Missense mutations of dynactin subunit p150Glued have been associated with multiple neurodegenerative diseases, including Perry syndrome, characterized by inherited parkinsonism, depression, weight loss, and hypoventilation. The current study investigated how the pathogenic mutant p150Glued affects the integrity and function of the nigrostriatal dopaminergic (DA) pathway in vivo. Methods: Using a tetracycline-controlled transcriptional regulation system, transgenic mouse models were generated with selective overexpression of wild-type, motor neuron disease-related G59S mutant, or Perry syndrome-related G71R mutant human p150Glued in midbrain DA neurons. A series of behavioral, neuropathological, neurochemical, electrochemical, and biochemical studies were performed on the mice to examine and compare the pathogenic impact of the two mutant p150Glued on the survival and function of midbrain DA neurons. Results: Compared with non-transgenic control mice, transgenic mice overexpressing wild-type human p150Glued showed neither motor phenotypes nor pathological, functional, or biochemical abnormalities of the nigrostriatal DA pathway. Transgenic mice overexpressing G59S mutant p150Glued displayed weight loss, motor deficits, early-onset defects in dopamine transmission, and early-onset loss of DA neurons and axons. Transgenic mice overexpressing G71R p150Glued mutant exhibited hyperactivities, impaired motor coordination, early-onset dysfunction of dopamine uptake, and late-onset loss of DA neurons and axons. In addition, overexpression of either G59S or G71R mutant p150Glued in midbrain DA neurons preferentially downregulated the expression of dopamine transporter at dopaminergic axon terminals. Furthermore, G59S mutant p150Glued rather than G71R mutant p150Glued formed aggregates in midbrain DA neurons in vivo, and the aggregates trapped dynein/dynactin, co-localized with lysosomes, and upregulated ubiquitination. Conclusion: These findings demonstrate that selective expression of either G59S or G71R mutant p150Glued in mouse midbrain DA neurons leads to progressive degeneration of the nigrostriatal DA pathway and indicate that G59S and G71R mutant p150Glued exhibit differential pathogenic impact on the survival and function of midbrain DA neurons in vivo.
{"title":"Selective expression of neurodegenerative diseases-related mutant p150Glued in midbrain dopaminergic neurons causes progressive degeneration of nigrostriatal pathway","authors":"Jia Yu, C. Sgobio, Xuan Yang, Yuehan Peng, X. Chen, Lixin Sun, Hoon Shim, H. Cai","doi":"10.20517/and.2022.07","DOIUrl":"https://doi.org/10.20517/and.2022.07","url":null,"abstract":"Aim: Missense mutations of dynactin subunit p150Glued have been associated with multiple neurodegenerative diseases, including Perry syndrome, characterized by inherited parkinsonism, depression, weight loss, and hypoventilation. The current study investigated how the pathogenic mutant p150Glued affects the integrity and function of the nigrostriatal dopaminergic (DA) pathway in vivo. Methods: Using a tetracycline-controlled transcriptional regulation system, transgenic mouse models were generated with selective overexpression of wild-type, motor neuron disease-related G59S mutant, or Perry syndrome-related G71R mutant human p150Glued in midbrain DA neurons. A series of behavioral, neuropathological, neurochemical, electrochemical, and biochemical studies were performed on the mice to examine and compare the pathogenic impact of the two mutant p150Glued on the survival and function of midbrain DA neurons. Results: Compared with non-transgenic control mice, transgenic mice overexpressing wild-type human p150Glued showed neither motor phenotypes nor pathological, functional, or biochemical abnormalities of the nigrostriatal DA pathway. Transgenic mice overexpressing G59S mutant p150Glued displayed weight loss, motor deficits, early-onset defects in dopamine transmission, and early-onset loss of DA neurons and axons. Transgenic mice overexpressing G71R p150Glued mutant exhibited hyperactivities, impaired motor coordination, early-onset dysfunction of dopamine uptake, and late-onset loss of DA neurons and axons. In addition, overexpression of either G59S or G71R mutant p150Glued in midbrain DA neurons preferentially downregulated the expression of dopamine transporter at dopaminergic axon terminals. Furthermore, G59S mutant p150Glued rather than G71R mutant p150Glued formed aggregates in midbrain DA neurons in vivo, and the aggregates trapped dynein/dynactin, co-localized with lysosomes, and upregulated ubiquitination. Conclusion: These findings demonstrate that selective expression of either G59S or G71R mutant p150Glued in mouse midbrain DA neurons leads to progressive degeneration of the nigrostriatal DA pathway and indicate that G59S and G71R mutant p150Glued exhibit differential pathogenic impact on the survival and function of midbrain DA neurons in vivo.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90726183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li Jiang, Xiao-yu Liu, Xiao-Qin Yan, Yu-Hui Liu, Yan-Jiang Wang, Ying Yang, Ling-Ru Wang
Aim: With the increasing number of patients recovered from COVID-19, the long-term health consequences of this disease have attracted much attention. Neurological complications are commonly seen in the acute phase of COVID-19, especially in older adults. This study aimed to investigate the long-term neurological sequelae in older COVID-19 survivors. Methods: A total of 1438 COVID-19 survivors were recruited in this study. One year after hospital discharge, information about self-reported symptoms of the central and peripheral nervous system was collected. Comparisons of these neurological symptoms between COVID-19 survivors with severe and nonsevere cases were performed. Results: A total of 139 (53.46%) COVID-19 survivors with severe cases and 328 (27.84%) survivors with nonsevere cases reported at least one neurological symptom one year after discharge. Most of these neurological symptoms were symptoms of the central nervous system. Specifically, 126 (48.46%) survivors with severe cases and 306 (25.98%) survivors with nonsevere cases reported at least one CNS symptom. The most frequently reported symptoms were memory deficit [234 (16.27%)] and attention deficit [80 (5.56%)]. Disease severity was associated with increased risks of long-term neurological sequelae of COVID-19. Conclusion: This study demonstrated that neurological sequelae of COVID-19 are common one year after patient discharge, suggesting that the effects of COVID-19 on the neurological system are prolonged.
{"title":"One-year self-reported neurological sequelae in older COVID-19 survivors","authors":"Li Jiang, Xiao-yu Liu, Xiao-Qin Yan, Yu-Hui Liu, Yan-Jiang Wang, Ying Yang, Ling-Ru Wang","doi":"10.20517/and.2022.10","DOIUrl":"https://doi.org/10.20517/and.2022.10","url":null,"abstract":"Aim: With the increasing number of patients recovered from COVID-19, the long-term health consequences of this disease have attracted much attention. Neurological complications are commonly seen in the acute phase of COVID-19, especially in older adults. This study aimed to investigate the long-term neurological sequelae in older COVID-19 survivors. Methods: A total of 1438 COVID-19 survivors were recruited in this study. One year after hospital discharge, information about self-reported symptoms of the central and peripheral nervous system was collected. Comparisons of these neurological symptoms between COVID-19 survivors with severe and nonsevere cases were performed. Results: A total of 139 (53.46%) COVID-19 survivors with severe cases and 328 (27.84%) survivors with nonsevere cases reported at least one neurological symptom one year after discharge. Most of these neurological symptoms were symptoms of the central nervous system. Specifically, 126 (48.46%) survivors with severe cases and 306 (25.98%) survivors with nonsevere cases reported at least one CNS symptom. The most frequently reported symptoms were memory deficit [234 (16.27%)] and attention deficit [80 (5.56%)]. Disease severity was associated with increased risks of long-term neurological sequelae of COVID-19. Conclusion: This study demonstrated that neurological sequelae of COVID-19 are common one year after patient discharge, suggesting that the effects of COVID-19 on the neurological system are prolonged.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"76 6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83469628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genetically modified animal models are commonly used for in vivo studies of human diseases. Mice are the most common animal models used in biomedical research, which have provided important insights into disease pathogenesis and are widely used to find treatments for diseases. However, due to the differences in the anatomical structure and physiological function between human and mouse brains, most genetically modified mouse models cannot fully recapitulate the overt and selective neuronal loss seen in age-dependent neurodegeneration diseases. While non-human primates (NHP) are closer to humans and have been used to model human disease, these models are difficult to be utilized at a large scale due to various limitations including their high costs, prolonged breeding time, community concerns for use of NHP, and high ethical standards. As an important animal resource in agriculture, pigs are also used as animal models in biomedical research. The central nervous system of pigs is highly similar to that of humans, making pig models suitable for investigating neurological diseases. The relatively short breeding period, large litter size, and established somatic cell transfer technology are advantages over NHP for using pigs to model human diseases. The recent development of gene editing tools allows one to more efficiently generate pig models that can precisely mimic genetic mutations in neurological diseases. In this review, we summarize recent advances in the use of pigs for modeling human neurological diseases, including new approaches for generating genetically modified pig models.
{"title":"Genetically engineered pig models of neurological diseases","authors":"Caijuan Li, Jun Li, L. Lai, Shihua Li, Sen Yan","doi":"10.20517/and.2022.13","DOIUrl":"https://doi.org/10.20517/and.2022.13","url":null,"abstract":"Genetically modified animal models are commonly used for in vivo studies of human diseases. Mice are the most common animal models used in biomedical research, which have provided important insights into disease pathogenesis and are widely used to find treatments for diseases. However, due to the differences in the anatomical structure and physiological function between human and mouse brains, most genetically modified mouse models cannot fully recapitulate the overt and selective neuronal loss seen in age-dependent neurodegeneration diseases. While non-human primates (NHP) are closer to humans and have been used to model human disease, these models are difficult to be utilized at a large scale due to various limitations including their high costs, prolonged breeding time, community concerns for use of NHP, and high ethical standards. As an important animal resource in agriculture, pigs are also used as animal models in biomedical research. The central nervous system of pigs is highly similar to that of humans, making pig models suitable for investigating neurological diseases. The relatively short breeding period, large litter size, and established somatic cell transfer technology are advantages over NHP for using pigs to model human diseases. The recent development of gene editing tools allows one to more efficiently generate pig models that can precisely mimic genetic mutations in neurological diseases. In this review, we summarize recent advances in the use of pigs for modeling human neurological diseases, including new approaches for generating genetically modified pig models.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90196513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by two pathological hallmark lesions: extracellular plaques composed of β-amyloid (Aβ) peptide and intracellular neurofibrillary tangles made up of highly phosphorylated tau protein. Over the past two decades, most disease-modifying therapies against AD have been developed mainly on the basis of the amyloid cascade hypothesis with a focus on Aβ. However, these agents yielded only limited benefits against disease progression, which prompts us to revitalize the long-neglected tau hypothesis. Tau protein is a microtubule-associated protein, which can stabilize microtubules, regulate microtubule assembly, and affect the morphology and growth of neuronal axons. Much more importantly, the degree of tau pathology is more closely related to cognitive decline in AD patients than that of Aβ pathology. Therefore, tau-targeting therapy seems to be a promising approach to combat AD. This review describes the research progress of tau-targeting therapy in AD, with an emphasis on immunotherapy. The current challenges and future perspectives in this field are also discussed.
{"title":"Tau-targeting therapy in Alzheimer’s disease: critical advances and future opportunities","authors":"Yi-Bo Guo, Song Li, Ling-Hui Zeng, Jun Tan","doi":"10.20517/and.2022.16","DOIUrl":"https://doi.org/10.20517/and.2022.16","url":null,"abstract":"Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by two pathological hallmark lesions: extracellular plaques composed of β-amyloid (Aβ) peptide and intracellular neurofibrillary tangles made up of highly phosphorylated tau protein. Over the past two decades, most disease-modifying therapies against AD have been developed mainly on the basis of the amyloid cascade hypothesis with a focus on Aβ. However, these agents yielded only limited benefits against disease progression, which prompts us to revitalize the long-neglected tau hypothesis. Tau protein is a microtubule-associated protein, which can stabilize microtubules, regulate microtubule assembly, and affect the morphology and growth of neuronal axons. Much more importantly, the degree of tau pathology is more closely related to cognitive decline in AD patients than that of Aβ pathology. Therefore, tau-targeting therapy seems to be a promising approach to combat AD. This review describes the research progress of tau-targeting therapy in AD, with an emphasis on immunotherapy. The current challenges and future perspectives in this field are also discussed.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":" 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91412213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuroinflammation in amyotrophic lateral sclerosis (ALS) is characterized by activation of monocytes/macrophages and T lymphocytes in the periphery and microglia and astrocytes within the central nervous system. This review emphasizes the role of oxidative stress in promoting systemic inflammation and the early stages of neurodegeneration. Motor axon terminals of ALS patients have significantly increased intraluminal calcium and dysfunctional mitochondria, increasing the formation of lipid peroxides and ferroptosis programmed cell death. Serum lipid peroxides and acute phase proteins are elevated, and regulatory T lymphocytes (Tregs) are dysfunctional, impairing immune-mediated neuroprotection. Macrophages are pro-inflammatory; the expression of genes involved in inflammation is increased in peripheral monocytes/macrophages of ALS patients. Suppressing these multiple components of inflammation is an important therapeutic goal and provides an opportunity to interrupt the self-propagating cytotoxic cycle. Two clinical trials with autologous infusions of ex vivo expanded Tregs have been safe and well tolerated, with promising clinical results associated with suppression of pro-inflammatory lipid peroxides.
{"title":"Oxidative stress-mediated inflammation promotes the pathogenesis of amyotrophic lateral sclerosis","authors":"S. Appel","doi":"10.20517/and.2022.26","DOIUrl":"https://doi.org/10.20517/and.2022.26","url":null,"abstract":"Neuroinflammation in amyotrophic lateral sclerosis (ALS) is characterized by activation of monocytes/macrophages and T lymphocytes in the periphery and microglia and astrocytes within the central nervous system. This review emphasizes the role of oxidative stress in promoting systemic inflammation and the early stages of neurodegeneration. Motor axon terminals of ALS patients have significantly increased intraluminal calcium and dysfunctional mitochondria, increasing the formation of lipid peroxides and ferroptosis programmed cell death. Serum lipid peroxides and acute phase proteins are elevated, and regulatory T lymphocytes (Tregs) are dysfunctional, impairing immune-mediated neuroprotection. Macrophages are pro-inflammatory; the expression of genes involved in inflammation is increased in peripheral monocytes/macrophages of ALS patients. Suppressing these multiple components of inflammation is an important therapeutic goal and provides an opportunity to interrupt the self-propagating cytotoxic cycle. Two clinical trials with autologous infusions of ex vivo expanded Tregs have been safe and well tolerated, with promising clinical results associated with suppression of pro-inflammatory lipid peroxides.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73599139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Novati, Elisabeth Singer-Mikosch, L. Yu-Taeger, E. Clemensson, H. Nguyen
No single animal model can recapitulate all the features of a particular human disease on its own. Historically, rats have been used to study neurobiology and underlying functional networks. Likewise, rat models have been created to study neurodegenerative mechanisms and therapeutic interventions. In the last decades, a shift towards the use of mice has been observed in many research fields, not least because of the comparatively easier genetic manipulation of mice. However, with the full sequence of the rat genome being available, advances in genetic manipulation of the rat, and advanced test regimens and biomarkers at hand, the rat presents itself once more as a valuable model organism for studying neurodegenerative disorders. This review provides an overview of currently available, well-characterized rat models of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as their advantages for studying neurodegenerative disorders and evaluating therapeutic interventions.
{"title":"Rat models of major neurodegenerative disorders","authors":"A. Novati, Elisabeth Singer-Mikosch, L. Yu-Taeger, E. Clemensson, H. Nguyen","doi":"10.20517/and.2022.19","DOIUrl":"https://doi.org/10.20517/and.2022.19","url":null,"abstract":"No single animal model can recapitulate all the features of a particular human disease on its own. Historically, rats have been used to study neurobiology and underlying functional networks. Likewise, rat models have been created to study neurodegenerative mechanisms and therapeutic interventions. In the last decades, a shift towards the use of mice has been observed in many research fields, not least because of the comparatively easier genetic manipulation of mice. However, with the full sequence of the rat genome being available, advances in genetic manipulation of the rat, and advanced test regimens and biomarkers at hand, the rat presents itself once more as a valuable model organism for studying neurodegenerative disorders. This review provides an overview of currently available, well-characterized rat models of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as their advantages for studying neurodegenerative disorders and evaluating therapeutic interventions.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77215381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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