Jessica Blumenfeld, Oscar Yip, Min Joo Kim, Yadong Huang
{"title":"Cell type-specific roles of APOE4 in Alzheimer disease","authors":"Jessica Blumenfeld, Oscar Yip, Min Joo Kim, Yadong Huang","doi":"10.1038/s41583-023-00776-9","DOIUrl":"10.1038/s41583-023-00776-9","url":null,"abstract":"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.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 2","pages":"91-110"},"PeriodicalIF":34.7,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139400534","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}
Alexandra L. Young, Neil P. Oxtoby, Sara Garbarino, Nick C. Fox, Frederik Barkhof, Jonathan M. Schott, Daniel C. Alexander
{"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}
{"title":"A neuronal subcompartment view of ATP production","authors":"Darran Yates","doi":"10.1038/s41583-023-00792-9","DOIUrl":"10.1038/s41583-023-00792-9","url":null,"abstract":"A study indicates that different mechanisms of ATP production predominate in different cellular subcompartments in neurons.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 3","pages":"142-142"},"PeriodicalIF":34.7,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139101376","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}
{"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}
{"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}
{"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}
{"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}
Ithai Rabinowitch, Daniel A. Colón-Ramos, Michael Krieg
{"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}
{"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}
{"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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