Tau polarizes an aging transcriptional signature to excitatory neurons and glia

Abstract
Data availability
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Abstract

Aging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell type-specific manner. Integration of cellular abundance and gene expression pinpoints Nuclear Factor Kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.

Data availability

All original single cell sequencing data have been uploaded to the Accelerating Medicines Parternship (AMP)-AD Knowledge Portal on Synapse and can be accessed through the DOI: https://doi.org/10.7303/syn35798807.1.

The following data sets were generated

1. Wu
2. T
3. Deger
4. JM
5. Ye
6. H
7. Guo
8. C
9. Dhindsa
10. J
11. Pekarek
12. BT
13. Al-Ouran
14. R
15. Liu
16. Z
17. Al-Ramahi
18. I
19. Botas
20. J
21. Shulman
22. JM
(2022) Tau polarizes an aging transcriptional signature to excitatory neurons and glia
Synapse: syn35798807.

https://doi.org/10.7303/syn35798807.1

The following previously published data sets were used

1. Mathys H
2. et al
(2019) The Single-cell transcriptomic analysis of Alzheimer's disease (snRNAseqPFC_BA10) Study
AD Knowledge Portal: syn2580853.

https://doi.org/10.7303/syn18485175
1. Grubman
2. et al
(2019) A single-cell atlas of the human cortex reveals drivers of transcriptional changes in Alzheimer's disease in specific cell subpopulations
NCBI Gene Expression Omnibus, GSE138852.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138852
1. Davie
2. et al
(2018) A single-cell transcriptome atlas of the ageing Drosophila brain
NCBI Gene Expression Omnibus, GSE107451.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE107451
1. Ozel
2. et al
(2020) Neuronal diversity and convergence in a visual system developmental atlas
NCBI Gene Expression Omnibus, GSE142789.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE142789
1. Mangleburg
2. et al
(2020) Integrated analysis of the aging brain transcriptome and proteome in tauopathy
Synapse: syn18485175.

https://doi.org/10.7303/syn7274101
1. Van de Sande
2. et al
(2020) pySCENIC: Drosophila transcription factors
Aerts lab resource.

https://github.com/aertslab/pySCENIC/tree/master/resources
1. Van de Sande
2. et al
(2020) pySCENIC: Motif-Gene rankings
Aerts lab resource.

https://resources.aertslab.org/cistarget/databases/old/drosophila_melanogaster/dm6/flybase_r6.02/mc8nr/gene_based/
1. Van de Sande
2. et al
(2020) psySCEnIC: Transcription factor to motif annotations
Aerts lab resource.

https://resources.aertslab.org/cistarget/motif2tf/

Article and author information

Author details

Timothy Wu

Medical Scientist Training Program, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5296-2023
Jennifer M Deger

Medical Scientist Training Program, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Hui Ye

Department of Neurology, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3965-9702
Caiwei Guo

Department of Neuroscience, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Justin Dhindsa

Medical Scientist Training Program, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Brandon T Pekarek

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Rami Al-Ouran

Department of Pediatrics, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Zhandong Liu

Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Ismael Al-Ramahi

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.
Juan Botas

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5476-5955
Joshua M Shulman

Department of Neurology, Baylor College of Medicine, Houston, United States

For correspondence
joshua.shulman@bcm.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1835-1971

Funding

National Institute on Aging (R01AG057339)

Zhandong Liu
Juan Botas
Joshua M Shulman

Huffington Foundation

Zhandong Liu
Juan Botas
Joshua M Shulman

McGee Family Foundation

Joshua M Shulman

Duncan Neurological Research Institute

Zhandong Liu
Ismael Al-Ramahi
Juan Botas
Joshua M Shulman

Effie Marie Caine Endowed Chair for Alzheimer's Research

Joshua M Shulman

National Institute on Aging (R01AG053960)

Joshua M Shulman

National Institute on Aging (U01AG061357)

Joshua M Shulman

National Institute on Aging (U01AG046161)

Joshua M Shulman

Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555)

Joshua M Shulman

National Institutes of Health (S10OD023469)

Joshua M Shulman

National Institutes of Health (S10OD025240)

Joshua M Shulman

Cancer Prevention and Research Institute of Texas (RP200504)

Joshua M Shulman

Parkinson's Foundation (PF-PRF-830012)

Hui Ye

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.