MaltSci 麦伴科研

Appearance

文献精选 > 近年高分"阿尔茨海默病"研究（IF≥30，近5年）

Single-cell multiregion dissection of Alzheimer's disease. ​

文献信息 ​

DOI10.1038/s41586-024-07606-7
PMID39048816
期刊Nature
影响因子48.5
JCR 分区Q1
发表年份2024
被引次数92
关键词阿尔茨海默病, 单细胞转录组, 神经元易感性
文献类型Journal Article
ISSN0028-0836
页码858-868
期号632(8026)
作者Hansruedi Mathys, Carles A Boix, Leyla Anne Akay, Ziting Xia, Jose Davila-Velderrain, Ayesha P Ng, Xueqiao Jiang, Ghada Abdelhady, Kyriaki Galani, Julio Mantero, Neil Band, Benjamin T James, Sudhagar Babu, Fabiola Galiana-Melendez, Kate Louderback, Dmitry Prokopenko, Rudolph E Tanzi, David A Bennett, Li-Huei Tsai, Manolis Kellis

一句话小结 ​

本研究通过对48名阿尔茨海默病患者及非患者的283个尸检人脑样本进行单细胞转录组分析，构建了老年人脑部六个区域的细胞图谱，识别出76种细胞类型，并发现阿尔茨海默病中兴奋性和抑制性神经元的脆弱群体减少，Reelin信号通路在其中发挥关键作用。该研究为理解阿尔茨海默病的病理机制及其对认知功能的影响提供了新的视角，有助于未来的疾病干预和治疗策略。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

阿尔茨海默病 · 单细胞转录组 · 神经元易感性

摘要 ​

阿尔茨海默病是全球痴呆症的主要原因，但其在大脑不同区域的病理进展所涉及的细胞通路仍然不甚了解。本文报告了一个关于老年人脑部六个不同区域的单细胞转录组图谱，涵盖来自48名阿尔茨海默病患者及非患者的283个尸检人脑样本中的130万细胞。我们识别出76种细胞类型，包括特定区域的星形胶质细胞和兴奋性神经元的亚型，以及独特于丘脑的抑制性中间神经元群体，这些群体与典型的抑制性亚类不同。我们发现，在阿尔茨海默病中，特定大脑区域内的兴奋性和抑制性神经元存在脆弱群体的减少，并提供证据表明Reelin信号通路参与调节这些神经元的脆弱性。我们开发了一种可扩展的方法用于发现基因模块，并利用该方法识别在阿尔茨海默病中发生改变的细胞类型特异性和区域特异性模块，注释与多种病理变量相关的转录组差异。我们识别出一个与阿尔茨海默病病理相关的认知韧性星形胶质细胞程序，将胆碱代谢和星形胶质细胞中的多胺生物合成与晚年保持的认知功能联系起来。总之，我们的研究构建了一个老年人脑部的区域图谱，并提供了对阿尔茨海默病病理的细胞脆弱性、反应和韧性的深入见解。

英文摘要 ​

Alzheimer's disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1-3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer's disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer's disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer's disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer's disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer's disease pathology.

麦伴智能科研服务 ​

智能阅读回答你对文献的任何问题，帮助理解文献中的复杂图表和公式
定位观点定位某个观点在文献中的蛛丝马迹
加入知识库完成数据提取，报告撰写等更多高级知识挖掘功能

主要研究问题 ​

  1. 在不同脑区中，阿尔茨海默病对特定细胞类型的影响有何不同？
  2. 该研究中提到的Reelin信号通路如何具体影响神经元的脆弱性？
  3. 除了已识别的细胞类型，是否还有其他潜在的细胞亚型在阿尔茨海默病中未被发现？
  4. 该研究的单细胞转录组学方法是否可以应用于其他神经退行性疾病的研究？
  5. 在认知韧性与阿尔茨海默病病理之间的关系中，其他代谢途径是否也扮演重要角色？

核心洞察 ​

研究背景和目的 ​

阿尔茨海默病（AD）是一种复杂的神经退行性疾病，其病理特征包括淀粉样斑块和神经纤维缠结。传统的研究方法通常依赖于组织样本的分析，而单细胞测序技术的兴起使得对疾病的细胞组成和基因表达模式进行更细致的研究成为可能。本研究旨在通过单细胞多区域分析，深入探讨阿尔茨海默病的细胞异质性和潜在的分子机制。

主要方法/材料/实验设计 ​

本研究采用了单细胞RNA测序（scRNA-seq）技术，对来自不同脑区的细胞进行分析。研究样本包括来自14种主要细胞类型的细胞，包括兴奋性神经元、抑制性神经元、星形胶质细胞等。使用UMAP（统一流形近似与投影）对细胞进行降维和可视化，并通过聚类分析识别不同细胞亚型。

以下是研究的技术路线图：

Mermaid diagram

关键结果和发现 ​

  1. 细胞异质性：通过单细胞分析，研究发现不同脑区的细胞类型分布存在显著差异，尤其是在抑制性神经元和星形胶质细胞中。
  2. 基因表达模式：特定的基因在不同细胞亚型中的表达差异明显，例如，兴奋性神经元中的NRGN和GPR137C在抑制性神经元中则表达较低。
  3. 功能富集分析：对基因模块的富集分析显示，多个模块与阿尔茨海默病的相关路径（如细胞周期、炎症反应等）显著相关。

主要结论/意义/创新性 ​

本研究通过单细胞多区域分析揭示了阿尔茨海默病中细胞类型的多样性和基因表达的复杂性。这一发现为理解AD的发病机制提供了新的视角，并可能为未来的治疗策略开发奠定基础。研究的创新性在于首次将单细胞RNA测序应用于多脑区的比较，揭示了疾病相关的细胞间交互作用。

研究局限性和未来方向 ​

  1. 样本量限制：尽管研究涵盖了多个脑区，但样本量仍相对有限，可能影响结果的普适性。
  2. 细胞环境影响：细胞在体外环境中的行为可能与在体内有所不同，未来研究应考虑细胞间的微环境效应。
  3. 长时间追踪：建议进行长期的纵向研究，以观察细胞变化与疾病进展的关系。

未来的研究方向包括扩大样本量，结合多组学数据（如蛋白质组学、代谢组学），以及探索特定细胞类型在阿尔茨海默病中的功能和机制。

参考文献 ​

  1. Staging of Alzheimer's disease-related neurofibrillary changes. - H Braak;E Braak - Neurobiology of aging (1995)
  2. Temporal course and pathologic basis of unawareness of memory loss in dementia. - Robert S Wilson;Patricia A Boyle;Lei Yu;Lisa L Barnes;Joel Sytsma;Aron S Buchman;David A Bennett;Julie A Schneider - Neurology (2015)
  3. Pathological correlates of dementia in a longitudinal, population-based sample of aging. - Joshua A Sonnen;Eric B Larson;Paul K Crane;Sebastien Haneuse;Ge Li;Gerald D Schellenberg;Suzanne Craft;James B Leverenz;Thomas J Montine - Annals of neurology (2007)
  4. Natural history of mild cognitive impairment in older persons. - D A Bennett;R S Wilson;J A Schneider;D A Evans;L A Beckett;N T Aggarwal;L L Barnes;J H Fox;J Bach - Neurology (2002)
  5. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. - David A Bennett;Julie A Schneider;Robert S Wilson;Julia L Bienias;Steven E Arnold - Archives of neurology (2004)
  6. Alzheimer's disease affects limbic nuclei of the thalamus. - H Braak;E Braak - Acta neuropathologica (1991)
  7. An anatomically comprehensive atlas of the adult human brain transcriptome. - Michael J Hawrylycz;Ed S Lein;Angela L Guillozet-Bongaarts;Elaine H Shen;Lydia Ng;Jeremy A Miller;Louie N van de Lagemaat;Kimberly A Smith;Amanda Ebbert;Zackery L Riley;Chris Abajian;Christian F Beckmann;Amy Bernard;Darren Bertagnolli;Andrew F Boe;Preston M Cartagena;M Mallar Chakravarty;Mike Chapin;Jimmy Chong;Rachel A Dalley;Barry David Daly;Chinh Dang;Suvro Datta;Nick Dee;Tim A Dolbeare;Vance Faber;David Feng;David R Fowler;Jeff Goldy;Benjamin W Gregor;Zeb Haradon;David R Haynor;John G Hohmann;Steve Horvath;Robert E Howard;Andreas Jeromin;Jayson M Jochim;Marty Kinnunen;Christopher Lau;Evan T Lazarz;Changkyu Lee;Tracy A Lemon;Ling Li;Yang Li;John A Morris;Caroline C Overly;Patrick D Parker;Sheana E Parry;Melissa Reding;Joshua J Royall;Jay Schulkin;Pedro Adolfo Sequeira;Clifford R Slaughterbeck;Simon C Smith;Andy J Sodt;Susan M Sunkin;Beryl E Swanson;Marquis P Vawter;Derric Williams;Paul Wohnoutka;H Ronald Zielke;Daniel H Geschwind;Patrick R Hof;Stephen M Smith;Christof Koch;Seth G N Grant;Allan R Jones - Nature (2012)
  8. Massively parallel single-nucleus RNA-seq with DroNc-seq. - Naomi Habib;Inbal Avraham-Davidi;Anindita Basu;Tyler Burks;Karthik Shekhar;Matan Hofree;Sourav R Choudhury;François Aguet;Ellen Gelfand;Kristin Ardlie;David A Weitz;Orit Rozenblatt-Rosen;Feng Zhang;Aviv Regev - Nature methods (2017)
  9. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. - Blue B Lake;Song Chen;Brandon C Sos;Jean Fan;Gwendolyn E Kaeser;Yun C Yung;Thu E Duong;Derek Gao;Jerold Chun;Peter V Kharchenko;Kun Zhang - Nature biotechnology (2018)
  10. A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation. - Alexandra Grubman;Gabriel Chew;John F Ouyang;Guizhi Sun;Xin Yi Choo;Catriona McLean;Rebecca K Simmons;Sam Buckberry;Dulce B Vargas-Landin;Daniel Poppe;Jahnvi Pflueger;Ryan Lister;Owen J L Rackham;Enrico Petretto;Jose M Polo - Nature neuroscience (2019)

引用本文的文献 ​

  1. CRISPRi-based screens in iAssembloids to elucidate neuron-glia interactions. - Emmy Li;Camila Benitez;Steven C Boggess;Mark Koontz;Indigo V L Rose;Delsy Martinez;Nina Draeger;Olivia M Teter;Avi J Samelson;Na'im Pierce;Erik M Ullian;Martin Kampmann - bioRxiv : the preprint server for biology (2024)
  2. ABCA7 Loss-of-Function Variants Impact Phosphatidylcholine Metabolism in the Human Brain. - Djuna von Maydell;Shannon Wright;Ping-Chieh Pao;Colin Staab;Oisín King;Andrea Spitaleri;Julia Maeve Bonner;Liwang Liu;Chung Jong Yu;Ching-Chi Chiu;Daniel Leible;Aine Ni Scannail;Mingpei Li;Carles A Boix;Hansruedi Mathys;Guillaume Leclerc;Gloria Suella Menchaca;Gwyneth Welch;Agnese Graziosi;Noelle Leary;George Samaan;Manolis Kellis;Li-Huei Tsai - bioRxiv : the preprint server for biology (2025)
  3. Predicting Alzheimer's Cognitive Resilience Score: A Comparative Study of Machine Learning Models Using RNA-seq Data. - Akihiro Kitani;Yusuke Matsui - bioRxiv : the preprint server for biology (2024)
  4. Spatiotemporal Dysregulation of Neuron-Glia Related Genes and Pro-/Anti-Inflammatory miRNAs in the 5xFAD Mouse Model of Alzheimer's Disease. - Marta Ianni;Miriam Corraliza-Gomez;Tiago Costa-Coelho;Mafalda Ferreira-Manso;Sara Inteiro-Oliveira;Nuno Alemãn-Serrano;Ana M Sebastião;Gonçalo Garcia;Maria José Diógenes;Dora Brites - International journal of molecular sciences (2024)
  5. gsQTL: Associating genetic risk variants with gene sets by exploiting their shared variability. - Gerard A Bouland;Niccolò Tesi;Ahmed Mahfouz;Marcel J T Reinders - bioRxiv : the preprint server for biology (2024)
  6. The ROSMAP project: aging and neurodegenerative diseases through omic sciences. - Alejandra P Pérez-González;Aidee Lashmi García-Kroepfly;Keila Adonai Pérez-Fuentes;Roberto Isaac García-Reyes;Fryda Fernanda Solis-Roldan;Jennifer Alejandra Alba-González;Enrique Hernández-Lemus;Guillermo de Anda-Jáuregui - Frontiers in neuroinformatics (2024)
  7. Lead Acetate Exposure and Cerebral Amyloid Accumulation: Mechanistic Evaluations in APP/PS1 Mice. - Huiying Gu;Luqing L Liu;Alanna Wu;Yongqi Yu;Uzay Emir;Stephen J Sawiak;Paul R Territo;Matin R Farlow;Wei Zheng;Yansheng Du - Environmental health perspectives (2024)
  8. Bibliometric and visual analysis of single-cell multiomics in neurodegenerative disease arrest studies. - Jieyan Wang;Shuqing Wang;Qingyu Li;Fei Liu;Yantong Wan;Hui Liang - Frontiers in neurology (2024)
  9. Mapping Alzheimer's disease: exploring cellular vulnerability and resilience. - Natalia Ortí-Casañ;John R Bethea;Ulrich L M Eisel - Signal transduction and targeted therapy (2024)
  10. Stress Vulnerability Exposed by Mapping Brain Network States to Single-Cell Transcriptomes. - Andre Fischer;Jelena Radulovic - Biological psychiatry (2024)

... (82 更多 篇文献)

© 2025 MaltSci 麦伴科研 - 我们用人工智能技术重塑科研