A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains

Andras Sziraki; Ziyu Lu; Jasper Lee; Gabor Banyai; Sonya Anderson; Abdulraouf Abdulraouf; Eli Metzner; Andrew Liao; Jason Banfelder; Alexander Epstein; Chloe Schaefer; Zihan Xu; Zehao Zhang; Li Gan; Peter T. Nelson; Wei Zhou; Junyue Cao

doi:10.1038/s41588-023-01572-y

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains

Andras Sziraki
, Ziyu Lu
, Jasper Lee
, Gabor Banyai
, Sonya Anderson
, Abdulraouf Abdulraouf
, Eli Metzner
, Andrew Liao
, Jason Banfelder
, Alexander Epstein
, Chloe Schaefer
, Zihan Xu
, Zehao Zhang
, Li Gan
, Peter T. Nelson
, Wei Zhou
, Junyue Cao

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

Abstract

Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial locations. This comprehensive view elucidates rare cell types expanded or depleted upon aging. We also investigated cell-type-specific responses to genetic alterations linked to Alzheimer’s disease, identifying associated rare cell types. Additionally, by profiling 118,240 human brain single-cell transcriptomes, we discerned cell- and region-specific transcriptomic changes tied to Alzheimer’s pathogenesis. In conclusion, this research offers a valuable resource for probing cell-type-specific dynamics in both normal and pathological aging.

Original language	English
Pages (from-to)	2104-2116
Number of pages	13
Journal	Nature Genetics
Volume	55
Issue number	12
DOIs	https://doi.org/10.1038/s41588-023-01572-y
State	Published - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

We thank all members of the Cao lab for helpful discussions and feedback. We thank J. Shendure (University of Washington) for insightful feedback on this work. We also thank members of the Rockefeller University Genomics Resource Center (SCR_020986), High-Performance Computing Resource Center and Comparative Bioscience Center for their exceptional assistance with library sequencing and animal maintenance. This work was funded by grants from the National Institutes of Health (DP2HG012522, R01AG076932 and RM1HG011014 to J.C.; P30AG072946 and P01AG078116 to P.T.N.; and R01AG072758 to L.G.) and the Sagol Network GerOmic Award (J.C.). This work is partly supported by the Pershing Square Foundation, Bill Ackman and Neri Oxman. We thank all members of the Cao lab for helpful discussions and feedback. We thank J. Shendure (University of Washington) for insightful feedback on this work. We also thank members of the Rockefeller University Genomics Resource Center (SCR_020986), High-Performance Computing Resource Center and Comparative Bioscience Center for their exceptional assistance with library sequencing and animal maintenance. This work was funded by grants from the National Institutes of Health (DP2HG012522, R01AG076932 and RM1HG011014 to J.C.; P30AG072946 and P01AG078116 to P.T.N.; and R01AG072758 to L.G.) and the Sagol Network GerOmic Award (J.C.). This work is partly supported by the Pershing Square Foundation, Bill Ackman and Neri Oxman.

Funders	Funder number
Bill Ackman and Neri Oxman
Comparative Bioscience Center
High-Performance Computing Resource Center
National Institutes of Health (NIH)	R01AG072758, RM1HG011014, DP2HG012522, P01AG078116, R01AG076932, P30AG072946
National Institutes of Health (NIH)
The George Washington University
Pershing Square Foundation
Rockefeller University	SCR_020986
Rockefeller University

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/s41588-023-01572-y

Cite this

Sziraki, A., Lu, Z., Lee, J., Banyai, G., Anderson, S., Abdulraouf, A., Metzner, E., Liao, A., Banfelder, J., Epstein, A., Schaefer, C., Xu, Z., Zhang, Z., Gan, L., Nelson, P. T., Zhou, W., & Cao, J. (2023). A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains. Nature Genetics, 55(12), 2104-2116. https://doi.org/10.1038/s41588-023-01572-y

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title = "A global view of aging and Alzheimer{\textquoteright}s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains",

abstract = "Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial locations. This comprehensive view elucidates rare cell types expanded or depleted upon aging. We also investigated cell-type-specific responses to genetic alterations linked to Alzheimer{\textquoteright}s disease, identifying associated rare cell types. Additionally, by profiling 118,240 human brain single-cell transcriptomes, we discerned cell- and region-specific transcriptomic changes tied to Alzheimer{\textquoteright}s pathogenesis. In conclusion, this research offers a valuable resource for probing cell-type-specific dynamics in both normal and pathological aging.",

author = "Andras Sziraki and Ziyu Lu and Jasper Lee and Gabor Banyai and Sonya Anderson and Abdulraouf Abdulraouf and Eli Metzner and Andrew Liao and Jason Banfelder and Alexander Epstein and Chloe Schaefer and Zihan Xu and Zehao Zhang and Li Gan and Nelson, \{Peter T.\} and Wei Zhou and Junyue Cao",

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doi = "10.1038/s41588-023-01572-y",

language = "English",

volume = "55",

pages = "2104--2116",

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Sziraki, A, Lu, Z, Lee, J, Banyai, G, Anderson, S, Abdulraouf, A, Metzner, E, Liao, A, Banfelder, J, Epstein, A, Schaefer, C, Xu, Z, Zhang, Z, Gan, L, Nelson, PT, Zhou, W & Cao, J 2023, 'A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains', Nature Genetics, vol. 55, no. 12, pp. 2104-2116. https://doi.org/10.1038/s41588-023-01572-y

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T1 - A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains

AU - Sziraki, Andras

AU - Lu, Ziyu

AU - Lee, Jasper

AU - Banyai, Gabor

AU - Anderson, Sonya

AU - Abdulraouf, Abdulraouf

AU - Metzner, Eli

AU - Liao, Andrew

AU - Banfelder, Jason

AU - Epstein, Alexander

AU - Schaefer, Chloe

AU - Xu, Zihan

AU - Zhang, Zehao

AU - Gan, Li

AU - Nelson, Peter T.

AU - Zhou, Wei

AU - Cao, Junyue

PY - 2023/12

Y1 - 2023/12

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AB - Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial locations. This comprehensive view elucidates rare cell types expanded or depleted upon aging. We also investigated cell-type-specific responses to genetic alterations linked to Alzheimer’s disease, identifying associated rare cell types. Additionally, by profiling 118,240 human brain single-cell transcriptomes, we discerned cell- and region-specific transcriptomic changes tied to Alzheimer’s pathogenesis. In conclusion, this research offers a valuable resource for probing cell-type-specific dynamics in both normal and pathological aging.

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A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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