Pub Date : 2024-01-08DOI: 10.1038/s41583-023-00776-9
Jessica Blumenfeld, Oscar Yip, Min Joo Kim, Yadong Huang
The ɛ4 allele of the apolipoprotein E gene (APOE), which translates to the APOE4 isoform, is the strongest genetic risk factor for late-onset Alzheimer disease (AD). Within the CNS, APOE is produced by a variety of cell types under different conditions, posing a challenge for studying its roles in AD pathogenesis. However, through powerful advances in research tools and the use of novel cell culture and animal models, researchers have recently begun to study the roles of APOE4 in AD in a cell type-specific manner and at a deeper and more mechanistic level than ever before. In particular, cutting-edge omics studies have enabled APOE4 to be studied at the single-cell level and have allowed the identification of critical APOE4 effects in AD-vulnerable cellular subtypes. Through these studies, it has become evident that APOE4 produced in various types of CNS cell — including astrocytes, neurons, microglia, oligodendrocytes and vascular cells — has diverse roles in AD pathogenesis. Here, we review these scientific advances and propose a cell type-specific APOE4 cascade model of AD. In this model, neuronal APOE4 emerges as a crucial pathological initiator and driver of AD pathogenesis, instigating glial responses and, ultimately, neurodegeneration. In addition, we provide perspectives on future directions for APOE4 research and related therapeutic developments in the context of AD. Within the CNS, APOE4 — a risk factor for late-onset Alzheimer disease — is produced by a variety of cell types. Blumenfeld, Yip, Kim and Huang discuss recent scientific advances that have begun to unravel the cell type-specific roles of APOE4 and outline a corresponding cell type-specific APOE4 cascade model of Alzheimer disease.
载脂蛋白 E 基因（APOE）的ɛ4 等位基因转化为 APOE4 同工型，是晚发性阿尔茨海默病（AD）的最强遗传风险因素。在中枢神经系统内，APOE 在不同条件下由多种细胞类型产生，这给研究其在阿尔茨海默病发病机制中的作用带来了挑战。然而，通过研究工具的强大进步以及新型细胞培养和动物模型的使用，研究人员最近开始以细胞类型特异性的方式，在比以往更深入、更机制化的水平上研究 APOE4 在 AD 中的作用。特别是，最前沿的全息研究使 APOE4 得以在单细胞水平上进行研究，并确定了 APOE4 在 AD 易感细胞亚型中的关键作用。通过这些研究，我们发现在中枢神经系统各类细胞（包括星形胶质细胞、神经元、小胶质细胞、少突胶质细胞和血管细胞）中产生的APOE4在AD发病机制中发挥着不同的作用。在此，我们回顾了这些科学进展，并提出了一种细胞类型特异性 APOE4 级联的 AD 模型。在这一模型中，神经元 APOE4 成为 AD 发病机制的关键病理启动因子和驱动因子，引发神经胶质细胞反应，最终导致神经退行性变。此外，我们还对APOE4研究的未来方向和AD相关疗法的发展进行了展望。
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Pub Date : 2024-01-08DOI: 10.1038/s41583-023-00779-6
Alexandra L. Young, Neil P. Oxtoby, Sara Garbarino, Nick C. Fox, Frederik Barkhof, Jonathan M. Schott, Daniel C. Alexander
Data-driven disease progression models are an emerging set of computational tools that reconstruct disease timelines for long-term chronic diseases, providing unique insights into disease processes and their underlying mechanisms. Such methods combine a priori human knowledge and assumptions with large-scale data processing and parameter estimation to infer long-term disease trajectories from short-term data. In contrast to ‘black box’ machine learning tools, data-driven disease progression models typically require fewer data and are inherently interpretable, thereby aiding disease understanding in addition to enabling classification, prediction and stratification. In this Review, we place the current landscape of data-driven disease progression models in a general framework and discuss their enhanced utility for constructing a disease timeline compared with wider machine learning tools that construct static disease profiles. We review the insights they have enabled across multiple neurodegenerative diseases, notably Alzheimer disease, for applications such as determining temporal trajectories of disease biomarkers, testing hypotheses about disease mechanisms and uncovering disease subtypes. We outline key areas for technological development and translation to a broader range of neuroscience and non-neuroscience applications. Finally, we discuss potential pathways and barriers to integrating disease progression models into clinical practice and trial settings. Data-driven disease progression models are computational tools that infer long-term disease timelines from short-term biomarker data and may provide insights into disease processes. In this Review, Young, Oxtoby et al. provide an overview of such models, with a focus on how they have been used in the context of neurodegenerative diseases, notably Alzheimer disease.
{"title":"Data-driven modelling of neurodegenerative disease progression: thinking outside the black box","authors":"Alexandra L. Young, Neil P. Oxtoby, Sara Garbarino, Nick C. Fox, Frederik Barkhof, Jonathan M. Schott, Daniel C. Alexander","doi":"10.1038/s41583-023-00779-6","DOIUrl":"10.1038/s41583-023-00779-6","url":null,"abstract":"Data-driven disease progression models are an emerging set of computational tools that reconstruct disease timelines for long-term chronic diseases, providing unique insights into disease processes and their underlying mechanisms. Such methods combine a priori human knowledge and assumptions with large-scale data processing and parameter estimation to infer long-term disease trajectories from short-term data. In contrast to ‘black box’ machine learning tools, data-driven disease progression models typically require fewer data and are inherently interpretable, thereby aiding disease understanding in addition to enabling classification, prediction and stratification. In this Review, we place the current landscape of data-driven disease progression models in a general framework and discuss their enhanced utility for constructing a disease timeline compared with wider machine learning tools that construct static disease profiles. We review the insights they have enabled across multiple neurodegenerative diseases, notably Alzheimer disease, for applications such as determining temporal trajectories of disease biomarkers, testing hypotheses about disease mechanisms and uncovering disease subtypes. We outline key areas for technological development and translation to a broader range of neuroscience and non-neuroscience applications. Finally, we discuss potential pathways and barriers to integrating disease progression models into clinical practice and trial settings. Data-driven disease progression models are computational tools that infer long-term disease timelines from short-term biomarker data and may provide insights into disease processes. In this Review, Young, Oxtoby et al. provide an overview of such models, with a focus on how they have been used in the context of neurodegenerative diseases, notably Alzheimer disease.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 2","pages":"111-130"},"PeriodicalIF":34.7,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139400480","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 : 2024-01-05DOI: 10.1038/s41583-023-00792-9
Darran Yates
A study indicates that different mechanisms of ATP production predominate in different cellular subcompartments in neurons.
一项研究表明，在神经元的不同细胞亚区中，ATP 的产生机制各不相同。
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Pub Date : 2024-01-05DOI: 10.1038/s41583-023-00787-6
Sian Lewis
Around 10% of individuals with frontotemporal lobar dementia have amyloid filament inclusions that lack tau and TDP-43 and were thought to contain the protein FUS, but are found instead to contain the FUS homologue TAF15.
{"title":"Mistaken identity","authors":"Sian Lewis","doi":"10.1038/s41583-023-00787-6","DOIUrl":"10.1038/s41583-023-00787-6","url":null,"abstract":"Around 10% of individuals with frontotemporal lobar dementia have amyloid filament inclusions that lack tau and TDP-43 and were thought to contain the protein FUS, but are found instead to contain the FUS homologue TAF15.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 2","pages":"78-78"},"PeriodicalIF":34.7,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139106407","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 : 2024-01-05DOI: 10.1038/s41583-023-00789-4
Lisa Heinke
Cytoplasmic mislocalization of TDP-43 in neurodegenerative disease affects mRNA maturation and protein levels of stathmin-2, leading to a reduction in axon diameter and tearing of outer myelin layers and thereby disrupting neuronal function.
{"title":"Orchestrating axonal organization","authors":"Lisa Heinke","doi":"10.1038/s41583-023-00789-4","DOIUrl":"10.1038/s41583-023-00789-4","url":null,"abstract":"Cytoplasmic mislocalization of TDP-43 in neurodegenerative disease affects mRNA maturation and protein levels of stathmin-2, leading to a reduction in axon diameter and tearing of outer myelin layers and thereby disrupting neuronal function.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 2","pages":"78-78"},"PeriodicalIF":34.7,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139101427","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 : 2024-01-04DOI: 10.1038/s41583-023-00790-x
Darran Yates
A study reveals a subpopulation of neuropeptide S-expressing neurons that regulates arousal and breathing.
一项研究揭示了一个表达神经肽 S 的神经元亚群，它能调节唤醒和呼吸。
{"title":"A neuronal cluster involved in arousal and breathing","authors":"Darran Yates","doi":"10.1038/s41583-023-00790-x","DOIUrl":"10.1038/s41583-023-00790-x","url":null,"abstract":"A study reveals a subpopulation of neuropeptide S-expressing neurons that regulates arousal and breathing.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 3","pages":"141-141"},"PeriodicalIF":34.7,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098291","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 : 2024-01-04DOI: 10.1038/s41583-023-00791-w
Darran Yates
A study in mice identifies formin 2 as a regulator of axon regeneration and a potential target for promoting nerve repair after peripheral nerve injury.
一项小鼠研究发现，甲形蛋白 2 是轴突再生的调节因子，也是促进周围神经损伤后神经修复的潜在靶点。
{"title":"Promoting axon regeneration after injury","authors":"Darran Yates","doi":"10.1038/s41583-023-00791-w","DOIUrl":"10.1038/s41583-023-00791-w","url":null,"abstract":"A study in mice identifies formin 2 as a regulator of axon regeneration and a potential target for promoting nerve repair after peripheral nerve injury.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 3","pages":"142-142"},"PeriodicalIF":34.7,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098292","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 : 2024-01-03DOI: 10.1038/s41583-023-00777-8
Ithai Rabinowitch, Daniel A. Colón-Ramos, Michael Krieg
Synapses are a key component of neural circuits, facilitating rapid and specific signalling between neurons. Synaptic engineering — the synthetic insertion of new synaptic connections into in vivo neural circuits — is an emerging approach for neural circuit interrogation. This approach is especially powerful for establishing causality in neural circuit structure–function relationships, for emulating synaptic plasticity and for exploring novel patterns of circuit connectivity. Contrary to other approaches for neural circuit manipulation, synaptic engineering targets specific connections between neurons and functions autonomously with no user-controlled external activation. Synaptic engineering has been successfully implemented in several systems and in different forms, including electrical synapses constructed from ectopically expressed connexin gap junction proteins, synthetic optical synapses composed of presynaptic photon-emitting luciferase coupled with postsynaptic light-gated channels, and artificial neuropeptide signalling pathways. This Perspective describes these different methods and how they have been applied, and examines how the field may advance. Synaptic engineering involves the synthetic insertion of new synapses between neurons in vivo. In this Perspective, Rabinowitch, Colón-Ramos and Krieg explore this emerging approach for studying neural circuits, describing the different methods that have been used and how they have been implemented.
{"title":"Understanding neural circuit function through synaptic engineering","authors":"Ithai Rabinowitch, Daniel A. Colón-Ramos, Michael Krieg","doi":"10.1038/s41583-023-00777-8","DOIUrl":"10.1038/s41583-023-00777-8","url":null,"abstract":"Synapses are a key component of neural circuits, facilitating rapid and specific signalling between neurons. Synaptic engineering — the synthetic insertion of new synaptic connections into in vivo neural circuits — is an emerging approach for neural circuit interrogation. This approach is especially powerful for establishing causality in neural circuit structure–function relationships, for emulating synaptic plasticity and for exploring novel patterns of circuit connectivity. Contrary to other approaches for neural circuit manipulation, synaptic engineering targets specific connections between neurons and functions autonomously with no user-controlled external activation. Synaptic engineering has been successfully implemented in several systems and in different forms, including electrical synapses constructed from ectopically expressed connexin gap junction proteins, synthetic optical synapses composed of presynaptic photon-emitting luciferase coupled with postsynaptic light-gated channels, and artificial neuropeptide signalling pathways. This Perspective describes these different methods and how they have been applied, and examines how the field may advance. Synaptic engineering involves the synthetic insertion of new synapses between neurons in vivo. In this Perspective, Rabinowitch, Colón-Ramos and Krieg explore this emerging approach for studying neural circuits, describing the different methods that have been used and how they have been implemented.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 2","pages":"131-139"},"PeriodicalIF":34.7,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087787","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 : 2023-12-22DOI: 10.1038/s41583-023-00786-7
Jake Rogers
A mark test of self-recognition in mice reveals that self-responding ventral CA1 neurons underlie mirror-induced self-directed behaviour and are shaped by social experience with conspecifics.
{"title":"Self-recognition mirrored from others","authors":"Jake Rogers","doi":"10.1038/s41583-023-00786-7","DOIUrl":"10.1038/s41583-023-00786-7","url":null,"abstract":"A mark test of self-recognition in mice reveals that self-responding ventral CA1 neurons underlie mirror-induced self-directed behaviour and are shaped by social experience with conspecifics.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 2","pages":"79-79"},"PeriodicalIF":34.7,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885514","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 : 2023-12-19DOI: 10.1038/s41583-023-00782-x
Katherine Whalley
A small population of neurons in the mouse brainstem coordinate sound production and volume control during vocalizations.
小鼠脑干中有一小部分神经元负责协调发声过程中的声音产生和音量控制。
{"title":"Controlling communication","authors":"Katherine Whalley","doi":"10.1038/s41583-023-00782-x","DOIUrl":"10.1038/s41583-023-00782-x","url":null,"abstract":"A small population of neurons in the mouse brainstem coordinate sound production and volume control during vocalizations.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 2","pages":"78-78"},"PeriodicalIF":34.7,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138740526","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}
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