Appearance
Single-cell multiregion dissection of Alzheimer's disease.
Literature Information
| DOI | 10.1038/s41586-024-07606-7 |
|---|---|
| PMID | 39048816 |
| Journal | Nature |
| Impact Factor | 48.5 |
| JCR Quartile | Q1 |
| Publication Year | 2024 |
| Times Cited | 92 |
| Keywords | Alzheimer's disease, single-cell transcriptomics, neurons, astrocytes, region-specific |
| Literature Type | Journal Article |
| ISSN | 0028-0836 |
| Pages | 858-868 |
| Issue | 632(8026) |
| Authors | 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 |
TL;DR
This study presents a comprehensive single-cell transcriptomic atlas of the aged human brain, analyzing 1.3 million cells from 283 post-mortem samples to uncover 76 distinct cell types, including specific subtypes linked to Alzheimer's disease. Key findings reveal vulnerable excitatory and inhibitory neuron populations, the involvement of the Reelin signaling pathway in neuronal vulnerability, and an astrocyte program associated with cognitive resilience, contributing valuable insights into the cellular mechanisms underlying Alzheimer's pathology and potential therapeutic targets.
Search for more papers on MaltSci.com
Alzheimer's disease · single-cell transcriptomics · neurons · astrocytes · region-specific
Abstract
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.
MaltSci.com AI Research Service
Intelligent ReadingAnswer any question about the paper and explain complex charts and formulas
Locate StatementsFind traces of a specific claim within the paper
Add to KBasePerform data extraction, report drafting, and advanced knowledge mining
Primary Questions Addressed
- How do the identified region-specific subtypes of astrocytes contribute to the overall pathology of Alzheimer's disease?
- What implications do the findings regarding the Reelin signaling pathway have for potential therapeutic strategies targeting neuronal vulnerability in Alzheimer's?
- In what ways might the astrocyte program linked to cognitive resilience influence future research on preventative measures for Alzheimer's disease?
- How does the cellular composition of different brain regions affect the progression and symptoms of Alzheimer's disease in affected individuals?
- What are the potential applications of the scalable method for discovering gene modules in other neurodegenerative diseases beyond Alzheimer's?
Key Findings
Summary of "Single-cell multiregion dissection of Alzheimer’s disease"
Research Background and Purpose
Alzheimer's disease (AD) is characterized by progressive neurodegeneration and is associated with various cellular changes in the brain. This study aims to provide a comprehensive analysis of cellular diversity and gene expression profiles across multiple brain regions in individuals with AD using single-cell RNA sequencing (scRNA-seq) techniques.
Main Methods/Materials/Experimental Design
The study utilized a multiregion approach, analyzing over 1.3 million single cells from various brain regions (e.g., angular gyrus, entorhinal cortex, hippocampus, midtemporal cortex, prefrontal cortex, and thalamus). The researchers employed UMAP (Uniform Manifold Approximation and Projection) for dimensionality reduction and clustering analysis to identify distinct cell types and their respective gene expression profiles.
Key Results and Findings
- Cellular Diversity: The study identified 14 major cell types, including excitatory neurons, inhibitory neurons, astrocytes, oligodendrocytes, and microglia.
- Gene Expression Profiles: Distinct gene expression patterns were observed in various cell types, with specific markers identified for each subtype. For instance, excitatory neurons showed significant expression of genes like RORB and GRIN2A, while inhibitory neurons expressed markers such as VIP and SST.
- Comparative Analysis: The results highlighted significant differences in gene expression between AD and control samples, revealing potential biomarkers for disease progression.
- Functional Enrichments: Gene set enrichment analysis indicated that many of the differentially expressed genes were involved in critical biological processes, such as synaptic transmission, inflammatory response, and cellular metabolism.
Main Conclusions/Significance/Innovation
The study provides a detailed characterization of cellular heterogeneity in the context of Alzheimer's disease. The findings suggest that specific cellular responses and gene expression changes may contribute to the pathophysiology of AD. This work lays the groundwork for future research aimed at identifying therapeutic targets and understanding the molecular mechanisms underlying neurodegeneration in AD.
Research Limitations and Future Directions
- Limitations: The study is limited by the cross-sectional nature of the data, which may not capture the dynamic changes in cellular profiles over time. Additionally, the analysis primarily focuses on gene expression without delving into protein-level changes.
- Future Directions: Future studies should aim to longitudinally assess cellular changes in AD progression, explore the functional implications of identified gene expression patterns, and integrate multi-omics approaches to provide a more comprehensive understanding of the disease.
Table of Key Findings
| Cell Type | Key Markers | Function |
|---|---|---|
| Excitatory Neurons | RORB, GRIN2A | Synaptic transmission |
| Inhibitory Neurons | VIP, SST | Modulation of neuronal activity |
| Astrocytes | GFAP, SLC1A2 | Support and metabolic functions |
| Oligodendrocytes | PLP1, CNP | Myelination and support of axons |
| Microglia | IBA1, CD68 | Immune response and maintenance |
Additional Insights
- The study underscores the potential for single-cell analyses to uncover complex interactions and alterations in cellular landscapes associated with Alzheimer's disease.
- The identification of unique gene expression profiles could facilitate the development of targeted interventions and biomarkers for early diagnosis and monitoring of AD.
References
- Staging of Alzheimer's disease-related neurofibrillary changes. - H Braak;E Braak - Neurobiology of aging (1995)
- 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)
- 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)
- 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)
- 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)
- Alzheimer's disease affects limbic nuclei of the thalamus. - H Braak;E Braak - Acta neuropathologica (1991)
- 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)
- 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)
- 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)
- 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)
Literatures Citing This Work
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Stress Vulnerability Exposed by Mapping Brain Network States to Single-Cell Transcriptomes. - Andre Fischer;Jelena Radulovic - Biological psychiatry (2024)
... (82 more literatures)
© 2025 MaltSci - We reshape scientific research with AI technology