Tau polarizes an aging transcriptional signature to excitatory neurons and glia
- Baylor College of Medicine, United States
- Texas Children's Hospital, United States
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.
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The Single-cell transcriptomic analysis of Alzheimer's disease (snRNAseqPFC_BA10) StudyAD Knowledge Portal: syn2580853.
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A single-cell transcriptome atlas of the ageing Drosophila brainNCBI Gene Expression Omnibus, GSE107451.
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Neuronal diversity and convergence in a visual system developmental atlasNCBI Gene Expression Omnibus, GSE142789.
Article and author information
Author details
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
© 2023, Wu et al.
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.
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Tau polarizes an aging transcriptional signature to excitatory neurons and glia
eLife 12:e85251.
https://doi.org/10.7554/eLife.85251
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