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bioRxiv · 10.1101/2022.11.14.516410

Tau polarizes an aging transcriptional signature to excitatory neurons and glia

Wu, T.·Deger, J. M.·Ye, H.·Guo, C.·Dhindsa, J.·Pekarek, B. T.·Al-Ouran, R.·Liu, Z.·Al-Ramahi, I.·Botas, J.·Shulman, J. M.
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Abstract

Aging is a major risk factor for Alzheimers 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 as a potential marker for neuronal 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.

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Wu, T., Deger, J. M., Ye, H., Guo, C., Dhindsa, J., Pekarek, B. T., Al-Ouran, R., Liu, Z., Al-Ramahi, I., Botas, J., Shulman, J. M.. 2022-11-16. Tau polarizes an aging transcriptional signature to excitatory neurons and glia. https://doi.org/10.1101/2022.11.14.516410

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