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Tau polarizes an aging transcriptional signature to excitatory neurons and glia.

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.

SUBMITTER: Wu T

PROVIDER: S-EPMC10259480 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Tau polarizes an aging transcriptional signature to excitatory neurons and glia.

Wu Timothy T Deger Jennifer M JM Ye Hui H Guo Caiwei C Dhindsa Justin J Pekarek Brandon T BT Al-Ouran Rami R Liu Zhandong Z Al-Ramahi Ismael I Botas Juan J Shulman Joshua M JM

eLife 20230523

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 <i>Drosophila</i> 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 ...[more]

PMID: 37219079

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Tau polarizes an aging transcriptional signature to excitatory neurons and glia.

Publications

Tau polarizes an aging transcriptional signature to excitatory neurons and glia.

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