Neurodegenerative diseases (NDs), encompassing Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are often characterized by the formation of pathological amyloid aggregates, predominantly composed of proteins like amyloid-β, tau, α-synuclein, TDP-43, and others. These amyloid aggregates inflict significant neuronal harm and incite inflammation. This review underscores the potential of small molecules as innovative therapeutic interventions, designed to influence the formation, stability, and breakdown of these pathological amyloid aggregates, which could potentially modify the disease’s progression and minimize its neurotoxic effects. This review first sketches the pathways and mechanisms involved in amyloid aggregation, followed by an in-depth analysis of recent advances in formulating small molecules that directly target these damaging aggregates. This includes various strategies such as inhibiting fibril formation, fostering off-pathway non-toxic oligomers or amorphous aggregates, disaggregating established pathological amyloid fibrils, and enhancing the protein quality control system to combat amyloid aggregation. In the end, this review identifies the challenges and opportunities involved in transitioning these molecules into effective treatments, focusing on critical factors such as penetration of the blood-brain barrier, target specificity, and safety considerations. This review, thus, presents a comprehensive overview of the potential role of small molecules in tackling NDs typified by amyloid aggregation.
{"title":"Development of small molecules for disrupting pathological amyloid aggregation in neurodegenerative diseases","authors":"Tianyi Cao, Xiang Li, Dan Li, Youqi Tao","doi":"10.20517/and.2023.25","DOIUrl":"https://doi.org/10.20517/and.2023.25","url":null,"abstract":"Neurodegenerative diseases (NDs), encompassing Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are often characterized by the formation of pathological amyloid aggregates, predominantly composed of proteins like amyloid-β, tau, α-synuclein, TDP-43, and others. These amyloid aggregates inflict significant neuronal harm and incite inflammation. This review underscores the potential of small molecules as innovative therapeutic interventions, designed to influence the formation, stability, and breakdown of these pathological amyloid aggregates, which could potentially modify the disease’s progression and minimize its neurotoxic effects. This review first sketches the pathways and mechanisms involved in amyloid aggregation, followed by an in-depth analysis of recent advances in formulating small molecules that directly target these damaging aggregates. This includes various strategies such as inhibiting fibril formation, fostering off-pathway non-toxic oligomers or amorphous aggregates, disaggregating established pathological amyloid fibrils, and enhancing the protein quality control system to combat amyloid aggregation. In the end, this review identifies the challenges and opportunities involved in transitioning these molecules into effective treatments, focusing on critical factors such as penetration of the blood-brain barrier, target specificity, and safety considerations. This review, thus, presents a comprehensive overview of the potential role of small molecules in tackling NDs typified by amyloid aggregation.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86999702","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}
{"title":"Animal models for research on neurodegenerative diseases","authors":"Xiao-Jiang Li","doi":"10.20517/and.2023.24","DOIUrl":"https://doi.org/10.20517/and.2023.24","url":null,"abstract":"","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85073742","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}
D. Beers, Jason R. Thonhoff, Aaron D. Thome, Alireza Faridar, Weihua Zhao, Shixiang Wen, S. Appel
Aim: Amyotrophic lateral sclerosis (ALS) is a systemic disease in which multiple dysfunctional pathways converge, culminating as this devastating disease. Immunological, oxidative, and structural analytes in cross-sectional and longitudinal patient sera samples were investigated and evaluated for their responses following autologous regulatory T lymphocyte (Treg)/IL-2 therapy. Methods: This retrospective cohort study was conducted at Houston Methodist Hospital and Massachusetts General Hospital in adults with sporadic ALS. Cross-sectional and longitudinal sera levels for each of the immunological (CCL2, IL-18), oxidative (4-HNE, MDA), and structural analytes (Nf-L, pNf-H) were assayed by ELISAs, and correlated with disease progression and clinical outcomes. Results: CCL2 and IL-18 levels were elevated in patients, especially rapidly progressing patients. 4-HNE was elevated in a subset of patients, whereas MDA was elevated in cross-sectional and longitudinally studied subjects. Nf-L was elevated in rapidly progressing patients, whereas pNf-H was decreased in these same patients. In the eleven patients assayed longitudinally, only three patients had increased levels of Nf-L or pNf-H; no patient had increased levels of both neurofilaments. Treg/IL-2 therapy suppressed levels of CCL2, IL-18, and 4-HNE. Conclusions: In these cohorts of patients with sporadic ALS, CCL2, IL-18, and 4-HNE accurately reflected disease progression on and off therapy; MDA was elevated but did not respond to therapy. The cross-sectional and longitudinal data were complementary. Nf-L and pNf-H did not reliably and consistently reflect disease progression. Immunological and oxidative pathological factors accurately reflected therapeutic responses in these pathways and are candidates to target clinical trial endpoints.
{"title":"Immunological, oxidative, and structural factors and their responses to regulatory t lymphocyte therapy in amyotrophic lateral sclerosis","authors":"D. Beers, Jason R. Thonhoff, Aaron D. Thome, Alireza Faridar, Weihua Zhao, Shixiang Wen, S. Appel","doi":"10.20517/and.2023.14","DOIUrl":"https://doi.org/10.20517/and.2023.14","url":null,"abstract":"Aim: Amyotrophic lateral sclerosis (ALS) is a systemic disease in which multiple dysfunctional pathways converge, culminating as this devastating disease. Immunological, oxidative, and structural analytes in cross-sectional and longitudinal patient sera samples were investigated and evaluated for their responses following autologous regulatory T lymphocyte (Treg)/IL-2 therapy. \u0000 Methods: This retrospective cohort study was conducted at Houston Methodist Hospital and Massachusetts General Hospital in adults with sporadic ALS. Cross-sectional and longitudinal sera levels for each of the immunological (CCL2, IL-18), oxidative (4-HNE, MDA), and structural analytes (Nf-L, pNf-H) were assayed by ELISAs, and correlated with disease progression and clinical outcomes. \u0000 Results: CCL2 and IL-18 levels were elevated in patients, especially rapidly progressing patients. 4-HNE was elevated in a subset of patients, whereas MDA was elevated in cross-sectional and longitudinally studied subjects. Nf-L was elevated in rapidly progressing patients, whereas pNf-H was decreased in these same patients. In the eleven patients assayed longitudinally, only three patients had increased levels of Nf-L or pNf-H; no patient had increased levels of both neurofilaments. Treg/IL-2 therapy suppressed levels of CCL2, IL-18, and 4-HNE. \u0000 Conclusions: In these cohorts of patients with sporadic ALS, CCL2, IL-18, and 4-HNE accurately reflected disease progression on and off therapy; MDA was elevated but did not respond to therapy. The cross-sectional and longitudinal data were complementary. Nf-L and pNf-H did not reliably and consistently reflect disease progression. Immunological and oxidative pathological factors accurately reflected therapeutic responses in these pathways and are candidates to target clinical trial endpoints.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82065524","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}
The transcriptional coactivator Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC1α) holds significant importance in the regulation of mitochondrial function during the pathogenesis of Alzheimer’s Disease (AD). PGC1α is highly expressed in the brain and has the ability to upregulate mitochondrial biogenesis. It modulates various metabolic pathways, such as the β-oxidation of fatty acids, which is important for generating ATP, and glycolysis, which supplies energy and protects against oxidative stress. The dysregulation of PGC1α can lead to alterations in energy metabolism in the brain, involving mitochondrial dysfunction and consequently decreasing cognitive function and neuronal pathologies. In the early stage of AD, the little amyloid-β protein (Aβ) induces the production of ROS, which upregulates the expression of PGC1α, resulting in increasing mitochondrial biogenesis, fatty acid oxidation and its mRNA expression. However, with the development of AD, a load of Aβ and neurofibrillary tangles ultimately lead to mitochondrial dysfunction, impaired mitochondrial respiration, reduced ATP production, and affect the behavioral brain function in AD. It provides a new idea for improvement or treatment of AD symptoms by activating PGC1α.
{"title":"Research progress on the role of PGC1α in mitochondrial dysfunction associated with Alzheimer’s disease","authors":"Zhi-qiang Li, Han Lin, Xiao-ping Huang, Shen-Qing Zhang, Xiao Shu, Xinan Wu","doi":"10.20517/and.2023.04","DOIUrl":"https://doi.org/10.20517/and.2023.04","url":null,"abstract":"The transcriptional coactivator Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC1α) holds significant importance in the regulation of mitochondrial function during the pathogenesis of Alzheimer’s Disease (AD). PGC1α is highly expressed in the brain and has the ability to upregulate mitochondrial biogenesis. It modulates various metabolic pathways, such as the β-oxidation of fatty acids, which is important for generating ATP, and glycolysis, which supplies energy and protects against oxidative stress. The dysregulation of PGC1α can lead to alterations in energy metabolism in the brain, involving mitochondrial dysfunction and consequently decreasing cognitive function and neuronal pathologies. In the early stage of AD, the little amyloid-β protein (Aβ) induces the production of ROS, which upregulates the expression of PGC1α, resulting in increasing mitochondrial biogenesis, fatty acid oxidation and its mRNA expression. However, with the development of AD, a load of Aβ and neurofibrillary tangles ultimately lead to mitochondrial dysfunction, impaired mitochondrial respiration, reduced ATP production, and affect the behavioral brain function in AD. It provides a new idea for improvement or treatment of AD symptoms by activating PGC1α.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75985454","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}
Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Neuronal damage is the main factor contributing to RTT, and the loss of MeCP2 function can result in reduced neuronal somas size, decreased dendritic abundance, and impaired neuronal function. While specific restoration of MeCP2 expression in neurons has been reported to partially rescue the behavioral phenotype and prolong the lifespan of mice, it cannot provide a complete cure. Therefore, other cells may be involved in the development of RTT. Although imaging and autopsy findings have revealed decreased white matter volume and corpus callosum thickness in RTT patients, the mechanisms underlying the development of white matter abnormalities remain unclear. These abnormalities are predominantly caused by damage to mature oligodendrocytes. This review provides an overview of the proliferation, differentiation, and function of oligodendrocyte lineage cells and elucidates the role of MeCP2 in these cells.
{"title":"Role of MeCP2 in oligodendrocyte lineage cells in Rett syndrome: review and inference","authors":"Zhen Zhang, Peng Li, Yongchang Chen","doi":"10.20517/and.2023.13","DOIUrl":"https://doi.org/10.20517/and.2023.13","url":null,"abstract":"Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Neuronal damage is the main factor contributing to RTT, and the loss of MeCP2 function can result in reduced neuronal somas size, decreased dendritic abundance, and impaired neuronal function. While specific restoration of MeCP2 expression in neurons has been reported to partially rescue the behavioral phenotype and prolong the lifespan of mice, it cannot provide a complete cure. Therefore, other cells may be involved in the development of RTT. Although imaging and autopsy findings have revealed decreased white matter volume and corpus callosum thickness in RTT patients, the mechanisms underlying the development of white matter abnormalities remain unclear. These abnormalities are predominantly caused by damage to mature oligodendrocytes. This review provides an overview of the proliferation, differentiation, and function of oligodendrocyte lineage cells and elucidates the role of MeCP2 in these cells.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89765649","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 the past decade, significant advancements have been made in understanding the brain regions and neuronal circuits regulating neurological behaviors. The endocannabinoid (eCB) system, which is ubiquitously distributed in the brain and extensively involved in synaptic modulation, has been believed to play potential roles in neuronal circuit processes and related disorders. Although eCB-based pharmacological studies have made some clinical achievements, they still often encounter conflicting reports or undesired effects due to global manipulation of manifold brain regions and neuronal circuits, which impede the therapeutic application of eCB-based medications. In this review, we are devoted to discussing the versatile forms of eCB-mediated synaptic plasticity and dissecting currently well-studied specific cannabinoid circuits involved in behavioral domains which are closely linked to the organism’s survival and life quality, such as pain perception and stress-related emotion disorders. By gaining new insights into selective cannabinoid control in circuits, we can potentially mitigate the drawbacks of traditional pharmacology and facilitate the development of precision medicine with novel therapeutic strategies and drug discoveries.
{"title":"Cannabinoid modulations of pain- and stress-related circuits","authors":"Ying Wang, Qingyu Wang, Li Tang, Xia Zhang","doi":"10.20517/and.2023.19","DOIUrl":"https://doi.org/10.20517/and.2023.19","url":null,"abstract":"In the past decade, significant advancements have been made in understanding the brain regions and neuronal circuits regulating neurological behaviors. The endocannabinoid (eCB) system, which is ubiquitously distributed in the brain and extensively involved in synaptic modulation, has been believed to play potential roles in neuronal circuit processes and related disorders. Although eCB-based pharmacological studies have made some clinical achievements, they still often encounter conflicting reports or undesired effects due to global manipulation of manifold brain regions and neuronal circuits, which impede the therapeutic application of eCB-based medications. In this review, we are devoted to discussing the versatile forms of eCB-mediated synaptic plasticity and dissecting currently well-studied specific cannabinoid circuits involved in behavioral domains which are closely linked to the organism’s survival and life quality, such as pain perception and stress-related emotion disorders. By gaining new insights into selective cannabinoid control in circuits, we can potentially mitigate the drawbacks of traditional pharmacology and facilitate the development of precision medicine with novel therapeutic strategies and drug discoveries.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79381757","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}
Alpha-synuclein (α-syn) is a presynaptic and nuclear protein that has been inextricably linked to Parkinson’s disease (PD). It regulates the presynaptic activities of neurons, but its aggregation and spreading have been associated with a group of diseases termed synucleinopathies. Here, we examined the commonly held view that α-syn caused disease and explored the concept that α-syn aggregation may be a consequence of pathobiology. Future therapies may need to encompass α-syn both a cause and consequence of the disease process.
{"title":"Can alpha-synuclein be both the cause and a consequence of Parkinson's disease?","authors":"Kang Chen, Yu-jie Guo, P. Lei, D. Finkelstein","doi":"10.20517/and.2023.05","DOIUrl":"https://doi.org/10.20517/and.2023.05","url":null,"abstract":"Alpha-synuclein (α-syn) is a presynaptic and nuclear protein that has been inextricably linked to Parkinson’s disease (PD). It regulates the presynaptic activities of neurons, but its aggregation and spreading have been associated with a group of diseases termed synucleinopathies. Here, we examined the commonly held view that α-syn caused disease and explored the concept that α-syn aggregation may be a consequence of pathobiology. Future therapies may need to encompass α-syn both a cause and consequence of the disease process.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91183404","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}
Cai Huimin, Fu Xiaofeng, Quan Shuiyue, Ren Ziye, Chu Changbiao, Jia Longfei
Alzheimer’s disease (AD) is common and devastating. However, current symptomatic treatments are unable to alter the progression of the disease. Fortunately, many ongoing trials of disease-modifying therapies may provide new insights into the treatment and prevention of AD. Due to the long-held amyloid cascade hypothesis, the development of pharmacotherapies targeting amyloid-β (Aβ) has been a major focus in AD research. The recent positive results and approval of several anti- Aβ monoclonal antibodies seem to be a milestone for AD treatment. In this review, we highlight the rationale and status of different Aβ-targeted therapies for AD, including those now on the market and those in clinical trials. We also discuss the challenges and future perspectives of Aβ-targeted therapies for AD.
阿尔茨海默病(AD)是一种常见且具有破坏性的疾病。然而，目前的对症治疗无法改变疾病的进展。幸运的是，许多正在进行的疾病改善疗法的试验可能为阿尔茨海默病的治疗和预防提供新的见解。由于长期以来的淀粉样蛋白级联假说，针对淀粉样蛋白β (a β)的药物治疗的开发一直是阿尔茨海默病研究的主要焦点。最近一些抗a β单克隆抗体的阳性结果和批准似乎是AD治疗的一个里程碑。在这篇综述中，我们重点介绍了不同的a β靶向治疗AD的基本原理和现状，包括那些已经上市的和正在临床试验的治疗方法。我们还讨论了a β靶向治疗AD的挑战和未来前景。
{"title":"Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future","authors":"Cai Huimin, Fu Xiaofeng, Quan Shuiyue, Ren Ziye, Chu Changbiao, Jia Longfei","doi":"10.20517/and.2023.16","DOIUrl":"https://doi.org/10.20517/and.2023.16","url":null,"abstract":"Alzheimer’s disease (AD) is common and devastating. However, current symptomatic treatments are unable to alter the progression of the disease. Fortunately, many ongoing trials of disease-modifying therapies may provide new insights into the treatment and prevention of AD. Due to the long-held amyloid cascade hypothesis, the development of pharmacotherapies targeting amyloid-β (Aβ) has been a major focus in AD research. The recent positive results and approval of several anti- Aβ monoclonal antibodies seem to be a milestone for AD treatment. In this review, we highlight the rationale and status of different Aβ-targeted therapies for AD, including those now on the market and those in clinical trials. We also discuss the challenges and future perspectives of Aβ-targeted therapies for AD.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"31 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135698923","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}
Increasing lines of evidence have indicated the beneficial impacts of exercise on the neurodegeneration and cognitive decline of Alzheimer’s disease (AD). While general mechanisms underlying the positive effects, including the elevated neurotrophins level, improved neurogenesis and neuroplasticity, restored angiogenesis and autophagy, and reduced neuroinflammation, have been well documented, the epigenetic mechanisms of exercise on AD, however, are still inconclusive. Exercise can regulate the expression of those AD-related genes or proteins through various epigenetic modulations, thereafter rescuing AD pathologies and improving cognitive deficits of AD. In this review, we briefly summarized recent research advances in the beneficial impacts of exercise on cognition and AD and discussed the underlying mechanisms from an epigenetic point of view, including DNA methylation, histone modifications, and non-coding RNAs. A deep understanding of how exercise epigenetically promotes cognitive and pathological recoveries in AD is crucial for the future discovery of precise exercise procedures or exercise-like remedies to treat this disease.
{"title":"Benefits of physical exercise on Alzheimer's disease: an epigenetic view","authors":"Song Li","doi":"10.20517/and.2022.37","DOIUrl":"https://doi.org/10.20517/and.2022.37","url":null,"abstract":"Increasing lines of evidence have indicated the beneficial impacts of exercise on the neurodegeneration and cognitive decline of Alzheimer’s disease (AD). While general mechanisms underlying the positive effects, including the elevated neurotrophins level, improved neurogenesis and neuroplasticity, restored angiogenesis and autophagy, and reduced neuroinflammation, have been well documented, the epigenetic mechanisms of exercise on AD, however, are still inconclusive. Exercise can regulate the expression of those AD-related genes or proteins through various epigenetic modulations, thereafter rescuing AD pathologies and improving cognitive deficits of AD. In this review, we briefly summarized recent research advances in the beneficial impacts of exercise on cognition and AD and discussed the underlying mechanisms from an epigenetic point of view, including DNA methylation, histone modifications, and non-coding RNAs. A deep understanding of how exercise epigenetically promotes cognitive and pathological recoveries in AD is crucial for the future discovery of precise exercise procedures or exercise-like remedies to treat this disease.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88217675","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}
Yun Fan, Wanbing Zhao, Y. Ni, Yiqi Liu, Yilin Tang, Yimin Sun, Feng-tao Liu, Wenbo Yu, Jianjun Wu, Jian Wang
Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) constitute a spectrum of diseases characterized by the abnormal aggregation of specific amyloid fibrillar proteins; these include β-amyloid (Aβ) and tau in the form of the extracellular Aβ plaques and neuronal neurofibrillary tangles in AD and fibrillar α-synuclein aggregation in the form of Lewy bodies and Lewy neurites in PD. Transmembrane protein 106B (TMEM106B) is a type II transmembrane lysosomal protein that participates in lysosome morphology, localization, acidification, and trafficking; t is involved in the pathogenesis of several NDs, especially frontotemporal lobular degeneration with TAR DNA-binding protein immunoreactive inclusions (FTLD-TDP). Studies from four independent research groups revealed that the luminal domain of TMEM106B (120-254aa) forms amyloid fibrils in several brain regions in patients with a series of NDs and neurologically normal older adults. Given its potentially critical roles in the pathogenesis of NDs and brain aging, this surprising finding has focused attention on TMEM106B and suggested that it is nearly as fundamental as other pathogenic amyloid proteins (e.g., Aβ, tau, α-syn); nevertheless, new questions surrounding TMEM106B must be asked. In this review,we firstly introduce the physiological function of TMEM106B and its involvement in NDs. Then, we elucidate the identification and cryo-electronic microscopic structure of TMEM106B fibrils and analyze the factors that contribute to the polymorphism of TMEM106B fibrils. Finally, the potential pathogenic role of TMEM106B fibrils is discussed, and the future directions for TMEM106 research in NDs are briefly summarized.
{"title":"Newly identified transmembrane protein 106B amyloid fibrils in the human brain: pathogens or by-products?","authors":"Yun Fan, Wanbing Zhao, Y. Ni, Yiqi Liu, Yilin Tang, Yimin Sun, Feng-tao Liu, Wenbo Yu, Jianjun Wu, Jian Wang","doi":"10.20517/and.2022.30","DOIUrl":"https://doi.org/10.20517/and.2022.30","url":null,"abstract":"Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) constitute a spectrum of diseases characterized by the abnormal aggregation of specific amyloid fibrillar proteins; these include β-amyloid (Aβ) and tau in the form of the extracellular Aβ plaques and neuronal neurofibrillary tangles in AD and fibrillar α-synuclein aggregation in the form of Lewy bodies and Lewy neurites in PD. Transmembrane protein 106B (TMEM106B) is a type II transmembrane lysosomal protein that participates in lysosome morphology, localization, acidification, and trafficking; t is involved in the pathogenesis of several NDs, especially frontotemporal lobular degeneration with TAR DNA-binding protein immunoreactive inclusions (FTLD-TDP). Studies from four independent research groups revealed that the luminal domain of TMEM106B (120-254aa) forms amyloid fibrils in several brain regions in patients with a series of NDs and neurologically normal older adults. Given its potentially critical roles in the pathogenesis of NDs and brain aging, this surprising finding has focused attention on TMEM106B and suggested that it is nearly as fundamental as other pathogenic amyloid proteins (e.g., Aβ, tau, α-syn); nevertheless, new questions surrounding TMEM106B must be asked. In this review,we firstly introduce the physiological function of TMEM106B and its involvement in NDs. Then, we elucidate the identification and cryo-electronic microscopic structure of TMEM106B fibrils and analyze the factors that contribute to the polymorphism of TMEM106B fibrils. Finally, the potential pathogenic role of TMEM106B fibrils is discussed, and the future directions for TMEM106 research in NDs are briefly summarized.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"167 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74218973","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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