Pub Date : 2024-04-24DOI: 10.1186/s13024-024-00726-8
Lynn van Olst, Alwin Kamermans, Sem Halters, Susanne M. A. van der Pol, Ernesto Rodriguez, Inge M. W. Verberk, Sanne G. S. Verberk, Danielle W. R. Wessels, Carla Rodriguez-Mogeda, Jan Verhoeff, Dorine Wouters, Jan Van den Bossche, Juan J. Garcia-Vallejo, Afina W. Lemstra, Maarten E. Witte, Wiesje M. van der Flier, Charlotte E. Teunissen, Helga E. de Vries
Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology. • Peripheral CD8+ TEMRA cells expressing markers associated with senescence accumulate in AD patients before dementia onset. • Peripheral immune cells correlate with AD biomarkers, varying by clinical AD stage. • APOE ε4 modifies peripheral immunity and its association with clinical AD measures.
阿尔茨海默病（AD）是最常见的痴呆症病因。最近的证据表明，外周免疫细胞参与了该疾病，但其潜在机制仍不清楚。与对照组相比，我们利用飞行时间细胞计数法（CyTOF）全面绘制了轻度认知障碍（MCI）或痴呆症患者的外周免疫变化图。我们发现了 AD 中的适应性免疫特征，并特别强调了在 AD 的 MCI 阶段，重新表达 CD45RA 的 PD1+ CD57+ CD8+ T 效应记忆细胞的积累。此外，一些先天性和适应性免疫细胞亚群与AD神经病理学的脑脊液（CSF）生物标志物和认知能力下降的测量指标相关。耐人寻味的是，记忆T细胞和B细胞亚群与AD患者脑脊液中的tau病理学、神经变性和神经炎症生物标志物呈负相关。最后，我们确定了 APOE ε4 等位基因对外周免疫的影响。我们的研究结果表明，外周免疫的重大改变与 AD 早期和晚期临床阶段都有关联，强调了进一步研究这些变化如何影响潜在脑病理学的必要性。- 表达衰老相关标记的外周 CD8+ TEMRA 细胞在痴呆症患者发病前就已积累。- 外周免疫细胞与AD生物标记物相关，因AD临床分期而异。- APOE ε4改变了外周免疫及其与临床AD指标的关系。
{"title":"Adaptive immune changes associate with clinical progression of Alzheimer’s disease","authors":"Lynn van Olst, Alwin Kamermans, Sem Halters, Susanne M. A. van der Pol, Ernesto Rodriguez, Inge M. W. Verberk, Sanne G. S. Verberk, Danielle W. R. Wessels, Carla Rodriguez-Mogeda, Jan Verhoeff, Dorine Wouters, Jan Van den Bossche, Juan J. Garcia-Vallejo, Afina W. Lemstra, Maarten E. Witte, Wiesje M. van der Flier, Charlotte E. Teunissen, Helga E. de Vries","doi":"10.1186/s13024-024-00726-8","DOIUrl":"https://doi.org/10.1186/s13024-024-00726-8","url":null,"abstract":"Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology. • Peripheral CD8+ TEMRA cells expressing markers associated with senescence accumulate in AD patients before dementia onset. • Peripheral immune cells correlate with AD biomarkers, varying by clinical AD stage. • APOE ε4 modifies peripheral immunity and its association with clinical AD measures.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"43 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-19DOI: 10.1186/s13024-024-00728-6
Asmaa Yehia, Osama A. Abulseoud
The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.
{"title":"Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration","authors":"Asmaa Yehia, Osama A. Abulseoud","doi":"10.1186/s13024-024-00728-6","DOIUrl":"https://doi.org/10.1186/s13024-024-00728-6","url":null,"abstract":"The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"22 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140620293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-16DOI: 10.1186/s13024-024-00720-0
Ya-Xi Luo, Ling-Ling Yang, Xiu-Qing Yao
Trillions of intestinal bacteria in the human body undergo dynamic transformations in response to physiological and pathological changes. Alterations in their composition and metabolites collectively contribute to the progression of Alzheimer’s disease. The role of gut microbiota in Alzheimer’s disease is diverse and complex, evidence suggests lipid metabolism may be one of the potential pathways. However, the mechanisms that gut microbiota mediate lipid metabolism in Alzheimer’s disease pathology remain unclear, necessitating further investigation for clarification. This review highlights the current understanding of how gut microbiota disrupts lipid metabolism and discusses the implications of these discoveries in guiding strategies for the prevention or treatment of Alzheimer’s disease based on existing data.
{"title":"Gut microbiota-host lipid crosstalk in Alzheimer’s disease: implications for disease progression and therapeutics","authors":"Ya-Xi Luo, Ling-Ling Yang, Xiu-Qing Yao","doi":"10.1186/s13024-024-00720-0","DOIUrl":"https://doi.org/10.1186/s13024-024-00720-0","url":null,"abstract":"Trillions of intestinal bacteria in the human body undergo dynamic transformations in response to physiological and pathological changes. Alterations in their composition and metabolites collectively contribute to the progression of Alzheimer’s disease. The role of gut microbiota in Alzheimer’s disease is diverse and complex, evidence suggests lipid metabolism may be one of the potential pathways. However, the mechanisms that gut microbiota mediate lipid metabolism in Alzheimer’s disease pathology remain unclear, necessitating further investigation for clarification. This review highlights the current understanding of how gut microbiota disrupts lipid metabolism and discusses the implications of these discoveries in guiding strategies for the prevention or treatment of Alzheimer’s disease based on existing data.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"41 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140557201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-14DOI: 10.1186/s13024-024-00721-z
Pasquale D’Acunzo, Elentina K. Argyrousi, Jonathan M. Ungania, Yohan Kim, Steven DeRosa, Monika Pawlik, Chris N. Goulbourne, Ottavio Arancio, Efrat Levy
Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer’s disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved. Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices. Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP. Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.
{"title":"Mitovesicles secreted into the extracellular space of brains with mitochondrial dysfunction impair synaptic plasticity","authors":"Pasquale D’Acunzo, Elentina K. Argyrousi, Jonathan M. Ungania, Yohan Kim, Steven DeRosa, Monika Pawlik, Chris N. Goulbourne, Ottavio Arancio, Efrat Levy","doi":"10.1186/s13024-024-00721-z","DOIUrl":"https://doi.org/10.1186/s13024-024-00721-z","url":null,"abstract":"Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer’s disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved. Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices. Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP. Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"66 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-08DOI: 10.1186/s13024-024-00719-7
Luuk E. de Vries, Inge Huitinga, Helmut W. Kessels, Dick F. Swaab, Joost Verhaagen
Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer’s Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood. In this review, we discuss the current definitions used in the field, highlight the translational approaches used to investigate resilience to AD and summarize the underlying cellular and molecular substrates of resilience that have been derived from human and animal studies, which have received more and more attention in the last few years. From these studies the picture emerges that resilient individuals are different from AD patients in terms of specific pathological species and their cellular reaction to AD pathology, which possibly helps to maintain cognition up to a certain tipping point. Studying these rare resilient individuals can be of great importance as it could pave the way to novel therapeutic avenues for AD.
尽管阿尔茨海默病（AD）的神经病理变化显著，但有些人仍能保持认知能力。这种认知与病理之间的差异被称为恢复力，并已发展成为一个广受争议的概念。认知刺激等外部因素与对老年痴呆症的恢复力有关，但确切的细胞和分子基础尚未完全明了。在这篇综述中，我们将讨论该领域目前使用的定义，重点介绍用于研究抗逆转录病毒能力的转化方法，并总结从人类和动物研究中得出的抗逆转录病毒能力的细胞和分子基础，这些研究在过去几年中受到越来越多的关注。从这些研究中可以看出，具有恢复力的个体在特定病理类型及其对 AD 病理的细胞反应方面与 AD 患者不同，这可能有助于将认知能力维持到某个临界点。研究这些罕见的恢复能力强的个体具有重要意义，因为它可以为新的注意力缺失症治疗途径铺平道路。
{"title":"The concept of resilience to Alzheimer’s Disease: current definitions and cellular and molecular mechanisms","authors":"Luuk E. de Vries, Inge Huitinga, Helmut W. Kessels, Dick F. Swaab, Joost Verhaagen","doi":"10.1186/s13024-024-00719-7","DOIUrl":"https://doi.org/10.1186/s13024-024-00719-7","url":null,"abstract":"Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer’s Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood. In this review, we discuss the current definitions used in the field, highlight the translational approaches used to investigate resilience to AD and summarize the underlying cellular and molecular substrates of resilience that have been derived from human and animal studies, which have received more and more attention in the last few years. From these studies the picture emerges that resilient individuals are different from AD patients in terms of specific pathological species and their cellular reaction to AD pathology, which possibly helps to maintain cognition up to a certain tipping point. Studying these rare resilient individuals can be of great importance as it could pave the way to novel therapeutic avenues for AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"32 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140538723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.1186/s13024-024-00724-w
María Llorián-Salvador, Alerie G. de Fuente, Christopher E. McMurran, Amy Dashwood, James Dooley, Adrian Liston, Rosana Penalva, Yvonne Dombrowski, Alan W. Stitt, Denise C. Fitzgerald
Ageing is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Regulatory T cells were selectively depleted in both young (2–4 months) and aged (18–23 months) FoxP3-DTR mice. We evaluated neuroretinal degeneration, gliosis, subretinal space phagocyte infiltration, and retinal pigmented epithelium morphology through immunofluorescence analysis. Subsequently, aged Treg depleted animals underwent adoptive transfer of both young and aged regulatory T cells from wild-type mice, and the resulting impact on neurodegeneration was assessed. Statistical analyses employed included the U-Mann Whitney test, and for comparisons involving more than two groups, 1-way ANOVA analysis followed by Bonferroni’s post hoc test. Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. Our findings demonstrate an essential role for regulatory T cells in maintaining age retinal homeostasis and preventing age-related neurodegeneration. This previously undescribed role of regulatory T cells in limiting retinal inflammation, RPE/choroid epithelium damage and subsequently photoreceptor loss with age, opens novel avenues to explore regulatory T cell neuroprotective and anti-inflammatory properties as potential therapeutic approaches for age-related retinal diseases.
老龄化是视网膜变性疾病的主要风险因素，也是发达国家最常见的致盲原因。这些疾病包括老年黄斑变性或糖尿病视网膜病变。调节性 T 细胞通过限制健康和疾病中的炎症和组织损伤，在神经系统的免疫调节中发挥着重要作用。由于视网膜长期以来被认为是免疫特权部位，调节性 T 细胞在视网膜稳态和与年龄相关的视网膜疾病中的确切贡献仍然未知。我们选择性地消耗了幼年（2-4 个月）和老年（18-23 个月）FoxP3-DTR 小鼠的调节性 T 细胞。我们通过免疫荧光分析评估了神经视网膜变性、胶质增生、视网膜下间隙吞噬细胞浸润和视网膜色素上皮形态。随后，老年Treg耗竭动物接受了来自野生型小鼠的年轻和老年调节性T细胞的收养性转移，并评估了其对神经退行性变的影响。采用的统计分析方法包括U-Mann Whitney检验，对于涉及两组以上的比较，则采用单因素方差分析，然后进行Bonferroni事后检验。我们的研究表明，调节性 T 细胞的清除会导致视网膜色素上皮细胞畸形和吞噬细胞在年轻小鼠和老年小鼠视网膜下间隙的聚集。然而，只有老年小鼠出现视网膜神经变性和胶质细胞病变。令人惊讶的是，年轻而非衰老的调节性 T 细胞的收养性转移能逆转这些变化。我们的研究结果表明，调节性 T 细胞在维持年龄视网膜稳态和防止与年龄相关的神经变性方面起着至关重要的作用。调节性 T 细胞在限制视网膜炎症、RPE/蛛网膜上皮细胞损伤以及随之而来的感光细胞随年龄增长而丧失方面的作用以前从未被描述过，这为探索调节性 T 细胞的神经保护和抗炎特性作为老年相关视网膜疾病的潜在治疗方法开辟了新的途径。
{"title":"Regulatory T cells limit age-associated retinal inflammation and neurodegeneration","authors":"María Llorián-Salvador, Alerie G. de Fuente, Christopher E. McMurran, Amy Dashwood, James Dooley, Adrian Liston, Rosana Penalva, Yvonne Dombrowski, Alan W. Stitt, Denise C. Fitzgerald","doi":"10.1186/s13024-024-00724-w","DOIUrl":"https://doi.org/10.1186/s13024-024-00724-w","url":null,"abstract":"Ageing is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Regulatory T cells were selectively depleted in both young (2–4 months) and aged (18–23 months) FoxP3-DTR mice. We evaluated neuroretinal degeneration, gliosis, subretinal space phagocyte infiltration, and retinal pigmented epithelium morphology through immunofluorescence analysis. Subsequently, aged Treg depleted animals underwent adoptive transfer of both young and aged regulatory T cells from wild-type mice, and the resulting impact on neurodegeneration was assessed. Statistical analyses employed included the U-Mann Whitney test, and for comparisons involving more than two groups, 1-way ANOVA analysis followed by Bonferroni’s post hoc test. Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. Our findings demonstrate an essential role for regulatory T cells in maintaining age retinal homeostasis and preventing age-related neurodegeneration. This previously undescribed role of regulatory T cells in limiting retinal inflammation, RPE/choroid epithelium damage and subsequently photoreceptor loss with age, opens novel avenues to explore regulatory T cell neuroprotective and anti-inflammatory properties as potential therapeutic approaches for age-related retinal diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"1 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.1186/s13024-024-00723-x
Marie-France Dorion, Diana Casas, Irina Shlaifer, Moein Yaqubi, Peter Fleming, Nathan Karpilovsky, Carol X.-Q. Chen, Michael Nicouleau, Valerio E. C. Piscopo, Emma J. MacDougall, Aeshah Alluli, Taylor M. Goldsmith, Alexandria Schneider, Samuel Dorion, Nathalia Aprahamian, Adam MacDonald, Rhalena A. Thomas, Roy W. R. Dudley, Jeffrey A. Hall, Edward A. Fon, Jack P. Antel, Jo Anne Stratton, Thomas M. Durcan, Roberta La Piana, Luke M. Healy
Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R. Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL. The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam3CSK4. Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1RWT/KO and CSF1RWT/E633K iMGL compared to their respective isogenic controls. We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities.
{"title":"An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders","authors":"Marie-France Dorion, Diana Casas, Irina Shlaifer, Moein Yaqubi, Peter Fleming, Nathan Karpilovsky, Carol X.-Q. Chen, Michael Nicouleau, Valerio E. C. Piscopo, Emma J. MacDougall, Aeshah Alluli, Taylor M. Goldsmith, Alexandria Schneider, Samuel Dorion, Nathalia Aprahamian, Adam MacDonald, Rhalena A. Thomas, Roy W. R. Dudley, Jeffrey A. Hall, Edward A. Fon, Jack P. Antel, Jo Anne Stratton, Thomas M. Durcan, Roberta La Piana, Luke M. Healy","doi":"10.1186/s13024-024-00723-x","DOIUrl":"https://doi.org/10.1186/s13024-024-00723-x","url":null,"abstract":"Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R. Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL. The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam3CSK4. Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1RWT/KO and CSF1RWT/E633K iMGL compared to their respective isogenic controls. We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"28 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1186/s13024-024-00722-y
Guy C Brown, Michael T Heneka
Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer's disease (AD) via peripheral infections or gut dysfunction elevating LPS levels in blood and brain, which promotes: amyloid pathology, tau pathology and microglial activation, contributing to the neurodegeneration of AD. The evidence supporting this hypothesis includes: i) blood and brain levels of LPS are elevated in AD patients, ii) AD risk factors increase LPS levels or response, iii) LPS induces Aβ expression, aggregation, inflammation and neurotoxicity, iv) LPS induces TAU phosphorylation, aggregation and spreading, v) LPS induces microglial priming, activation and neurotoxicity, and vi) blood LPS induces loss of synapses, neurons and memory in AD mouse models, and cognitive dysfunction in humans. However, to test the hypothesis, it is necessary to test whether reducing blood LPS reduces AD risk or progression. If the LPS endotoxin hypothesis is correct, then treatments might include: reducing infections, changing gut microbiome, reducing leaky gut, decreasing blood LPS, or blocking LPS response.
脂多糖（LPS）占革兰氏阴性细菌表面的大部分，如果 LPS 进入人体或大脑，就会诱发炎症并成为一种内毒素。我们在此提出一个假设，即 LPS 可能会通过外周感染或肠道功能紊乱导致血液和大脑中的 LPS 水平升高，从而促进淀粉样蛋白病变、tau 病变和小胶质细胞活化，导致阿尔茨海默病（AD）的病理生理学。支持这一假说的证据包括：i) AD 患者血液和大脑中的 LPS 水平升高；ii) AD 风险因素会增加 LPS 水平或反应；iii) LPS 会诱导 Aβ 的表达、聚集、炎症和神经毒性；iv) LPS 会诱导 TAU 磷酸化、聚集和扩散；v) LPS 会诱导小胶质细胞的启动、激活和神经毒性；vi) 血液中的 LPS 会诱导 AD 小鼠模型中突触、神经元和记忆的丧失，以及人类的认知功能障碍。然而，要验证这一假说，就必须检验减少血液中的 LPS 是否会降低 AD 风险或减少其进展。如果 LPS 内毒素假说是正确的，那么治疗方法可能包括：减少感染、改变肠道微生物群、减少肠道渗漏、减少血液中的 LPS 或阻断 LPS 反应。
{"title":"The endotoxin hypothesis of Alzheimer's disease.","authors":"Guy C Brown, Michael T Heneka","doi":"10.1186/s13024-024-00722-y","DOIUrl":"10.1186/s13024-024-00722-y","url":null,"abstract":"<p><p>Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer's disease (AD) via peripheral infections or gut dysfunction elevating LPS levels in blood and brain, which promotes: amyloid pathology, tau pathology and microglial activation, contributing to the neurodegeneration of AD. The evidence supporting this hypothesis includes: i) blood and brain levels of LPS are elevated in AD patients, ii) AD risk factors increase LPS levels or response, iii) LPS induces Aβ expression, aggregation, inflammation and neurotoxicity, iv) LPS induces TAU phosphorylation, aggregation and spreading, v) LPS induces microglial priming, activation and neurotoxicity, and vi) blood LPS induces loss of synapses, neurons and memory in AD mouse models, and cognitive dysfunction in humans. However, to test the hypothesis, it is necessary to test whether reducing blood LPS reduces AD risk or progression. If the LPS endotoxin hypothesis is correct, then treatments might include: reducing infections, changing gut microbiome, reducing leaky gut, decreasing blood LPS, or blocking LPS response.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"30"},"PeriodicalIF":15.1,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10983749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-27DOI: 10.1186/s13024-024-00718-8
Anna Calliari, Lillian M. Daughrity, Ellen A. Albagli, Paula Castellanos Otero, Mei Yue, Karen Jansen-West, Naeyma N. Islam, Thomas Caulfield, Bailey Rawlinson, Michael DeTure, Casey Cook, Neill R. Graff-Radford, Gregory S. Day, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Keith A. Josephs, Björn Oskarsson, Aaron D. Gitler, Dennis W. Dickson, Tania F. Gendron, Mercedes Prudencio, Michael E. Ward, Yong-Jie Zhang, Leonard Petrucelli
This letter demonstrates the potential of novel cryptic proteins resulting from TAR DNA-binding protein 43 (TDP-43) dysfunction as markers of TDP-43 pathology in neurodegenerative diseases.
这封信证明，TAR DNA 结合蛋白 43（TDP-43）功能障碍导致的新型隐匿蛋白有可能成为神经退行性疾病中 TDP-43 病理学的标志物。
{"title":"HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases","authors":"Anna Calliari, Lillian M. Daughrity, Ellen A. Albagli, Paula Castellanos Otero, Mei Yue, Karen Jansen-West, Naeyma N. Islam, Thomas Caulfield, Bailey Rawlinson, Michael DeTure, Casey Cook, Neill R. Graff-Radford, Gregory S. Day, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Keith A. Josephs, Björn Oskarsson, Aaron D. Gitler, Dennis W. Dickson, Tania F. Gendron, Mercedes Prudencio, Michael E. Ward, Yong-Jie Zhang, Leonard Petrucelli","doi":"10.1186/s13024-024-00718-8","DOIUrl":"https://doi.org/10.1186/s13024-024-00718-8","url":null,"abstract":"This letter demonstrates the potential of novel cryptic proteins resulting from TAR DNA-binding protein 43 (TDP-43) dysfunction as markers of TDP-43 pathology in neurodegenerative diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"32 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140303784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-25DOI: 10.1186/s13024-024-00717-9
Araks Martirosyan, Rizwan Ansari, Francisco Pestana, Katja Hebestreit, Hayk Gasparyan, Razmik Aleksanyan, Silvia Hnatova, Suresh Poovathingal, Catherine Marneffe, Dietmar R. Thal, Andrew Kottick, Victor J. Hanson-Smith, Sebastian Guelfi, William Plumbly, T. Grant Belgard, Emmanouil Metzakopian, Matthew G. Holt
<p> Molecular Neurodegeneration (2024) 19:7</p><p> https://doi.org/10.1186/s13024-023-00699-0.</p><p> The original article contained an error whereby the production team handling the article mistakenly omitted the company of affiliation #8 (‘ bit.bio’).</p><p> The affiliation text has since been corrected, and is also viewable in this Correction article.</p><span>Author notes</span><ol><li><p>Araks Martirosyan, Rizwan Ansari and Francisco Pestana contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>VIB Center for Brain & Disease Research, KU Leuven, Leuven, Belgium</p><p>Araks Martirosyan, Francisco Pestana, Suresh Poovathingal, Catherine Marneffe & Matthew G. Holt</p></li><li><p>Department of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, CB2 0AH, Cambridge, UK</p><p>Rizwan Ansari, Silvia Hnatova, William Plumbly & Emmanouil Metzakopian</p></li><li><p>Verge Genomics, South San Francisco, CA, USA</p><p>Katja Hebestreit, Andrew Kottick, Victor J. Hanson-Smith & Sebastian Guelfi</p></li><li><p>Armenian Bioinformatics Institute, Yerevan, Armenia</p><p>Hayk Gasparyan & Razmik Aleksanyan</p></li><li><p>Department of Mathematics and Mechanics, Yerevan State University, Yerevan, Armenia</p><p>Hayk Gasparyan & Razmik Aleksanyan</p></li><li><p>Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute, Department of Pathology, KU Leuven, UZ Leuven, Leuven, Belgium</p><p>Dietmar R. Thal</p></li><li><p>The Bioinformatics CRO, Orlando, FL, USA</p><p>T. Grant Belgard</p></li><li><p>bit.bio, The Dorothy Hodgkin Building, Babraham Research Institute, Cambridge CB223FH,, Cambridge, UK</p><p>Emmanouil Metzakopian</p></li><li><p>Laboratory of Synapse Biology, i3S, Porto, Portugal</p><p>Matthew G. Holt</p></li></ol><span>Authors</span><ol><li><span>Araks Martirosyan</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rizwan Ansari</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Francisco Pestana</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Katja Hebestreit</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Hayk Gasparyan</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Razmik Aleksanyan</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Silvia Hnatova</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Suresh Poovathingal</span>View
Molecular Neurodegeneration (2024) 19:7https://doi.org/10.1186/s13024-023-00699-0。原文中有一处错误，即处理文章的制作团队错误地遗漏了8号隶属公司（'bit.bio'）。作者注释Araks Martirosyan、Rizwan Ansari和Francisco Pestana对本研究做出了同样的贡献。作者和单位比利时鲁汶大学鲁汶分校VIB脑与疾病研究中心Araks Martirosyan、Francisco Pestana、Suresh Poovathingal、Catherine Marneffe & Matthew G. Holt临床神经病学系。HoltDepartment of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, CB2 0AH, Cambridge, UKRizwan Ansari, Silvia Hnatova, William Plumbly & Emmanouil MetzakopianVerge Genomics, South San Francisco, CA, USAKatja Hebestreit, Andrew Kottick, Victor J. Hanson-Smith & Emmanouil MetzakopianVerge Genomics, South San Francisco, CA, USAKatja Hebestreit, Andrew Kottick, Victor J. Hanson-Smith &; Emmanouil MetzakopianHanson-Smith & Sebastian GuelfiArmenian Bioinformatics Institute, Yerevan, ArmeniaHayk Gasparyan & Razmik AleksanyanDepartment of Mathematics and Mechanics, Yerevan State University, Yerevan, ArmeniaHayk Gasparyan &；Razmik AleksanyanLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute, Department of Pathology, KU Leuven, UZ Leuven, Leuven, BelgiumDietmar R．ThalThe Bioinformatics CRO, Orlando, FL, USAT.Grant Belgardbit.bio，The Dorothy Hodgkin Building，Babraham Research Institute，Cambridge CB223FH，Cambridge，UKEmmanouil MetzakopianLaboratory of Synapse Biology，i3S，Porto，PortugalMatthew G．Holt作者简介Araks Martirosyan查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Rizwan Ansari查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Francisco Pestana查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Katja Hebestreit查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Hayk Gasparyan查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Google Scholar中搜索该作者Razmik AleksanyanView作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Silvia HnatovaView作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Suresh PoovathingalView作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Catherine MarneffeView作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Dietmar R. Thal.ThalView 作者发表作品您也可以在 PubMed Google ScholarAndrew KottickView 作者发表作品您也可以在 PubMed Google ScholarVictor J. Hanson-SmithView 作者发表作品您也可以在 PubMed Google ScholarSebastian GuelfiView 作者发表作品您也可以在 PubMed Google ScholarWilliam PlumblyView 作者发表作品您也可以在 PubMed Google ScholarT.Grant BelgardView author publications您也可以在PubMed Google Scholar中搜索该作者Emmanouil MetzakopianView author publications您也可以在PubMed Google Scholar中搜索该作者Matthew G. HoltView author publications您也可以在PubMed Google Scholar中搜索该作者Corresponding authors通信作者：Emmanouil Metzakopian或Matthew G. Holt.Publisher's NoteSpringer Nature对出版地图和机构隶属关系中的管辖权主张保持中立。本文采用知识共享署名 4.0 国际许可协议（Creative Commons Attribution 4.0 International License）进行许可，允许以任何媒介或形式使用、共享、改编、分发和复制，但必须注明原作者和来源，提供知识共享许可协议的链接，并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中，除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中，且您打算使用的材料不符合法律规定或超出许可使用范围，您需要直接从版权所有者处获得许可。要查看该许可的副本，请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明，否则知识共享公共领域专用免责声明 (http://creativecommons.org/publicdomain/zero/1.0/)
{"title":"Correction: Unravelling cell type-specific responses to Parkinson’s Disease at single cell resolution","authors":"Araks Martirosyan, Rizwan Ansari, Francisco Pestana, Katja Hebestreit, Hayk Gasparyan, Razmik Aleksanyan, Silvia Hnatova, Suresh Poovathingal, Catherine Marneffe, Dietmar R. Thal, Andrew Kottick, Victor J. Hanson-Smith, Sebastian Guelfi, William Plumbly, T. Grant Belgard, Emmanouil Metzakopian, Matthew G. Holt","doi":"10.1186/s13024-024-00717-9","DOIUrl":"https://doi.org/10.1186/s13024-024-00717-9","url":null,"abstract":"<p> Molecular Neurodegeneration (2024) 19:7</p><p>\u0000https://doi.org/10.1186/s13024-023-00699-0.</p><p> The original article contained an error whereby the production team handling the article mistakenly omitted the company of affiliation #8 (‘ bit.bio’).</p><p> The affiliation text has since been corrected, and is also viewable in this Correction article.</p><span>Author notes</span><ol><li><p>Araks Martirosyan, Rizwan Ansari and Francisco Pestana contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>VIB Center for Brain & Disease Research, KU Leuven, Leuven, Belgium</p><p>Araks Martirosyan, Francisco Pestana, Suresh Poovathingal, Catherine Marneffe & Matthew G. Holt</p></li><li><p>Department of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, CB2 0AH, Cambridge, UK</p><p>Rizwan Ansari, Silvia Hnatova, William Plumbly & Emmanouil Metzakopian</p></li><li><p>Verge Genomics, South San Francisco, CA, USA</p><p>Katja Hebestreit, Andrew Kottick, Victor J. Hanson-Smith & Sebastian Guelfi</p></li><li><p>Armenian Bioinformatics Institute, Yerevan, Armenia</p><p>Hayk Gasparyan & Razmik Aleksanyan</p></li><li><p>Department of Mathematics and Mechanics, Yerevan State University, Yerevan, Armenia</p><p>Hayk Gasparyan & Razmik Aleksanyan</p></li><li><p>Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute, Department of Pathology, KU Leuven, UZ Leuven, Leuven, Belgium</p><p>Dietmar R. Thal</p></li><li><p>The Bioinformatics CRO, Orlando, FL, USA</p><p>T. Grant Belgard</p></li><li><p>bit.bio, The Dorothy Hodgkin Building, Babraham Research Institute, Cambridge CB223FH,, Cambridge, UK</p><p>Emmanouil Metzakopian</p></li><li><p>Laboratory of Synapse Biology, i3S, Porto, Portugal</p><p>Matthew G. Holt</p></li></ol><span>Authors</span><ol><li><span>Araks Martirosyan</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rizwan Ansari</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Francisco Pestana</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Katja Hebestreit</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Hayk Gasparyan</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Razmik Aleksanyan</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Silvia Hnatova</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Suresh Poovathingal</span>View ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"77 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140209763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：