Tau polarizes an aging transcriptional signature to excitatory neurons and glia

Elife. 2023 May 23:12:e85251. doi: 10.7554/eLife.85251.


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.

Keywords: Alzheimer's disease; D. melanogaster; Drosophila; aging; genetics; genomics; human; innate immune; neuroscience; nuclear factor kappa B; tauopathy.

MeSH terms

  • Aging / genetics
  • Alzheimer Disease* / metabolism
  • Animals
  • Brain / metabolism
  • Drosophila / metabolism
  • Humans
  • Neuroglia / metabolism
  • Neurons / metabolism
  • tau Proteins* / genetics
  • tau Proteins* / metabolism


  • tau Proteins

Associated data

  • GEO/GSE138852
  • GEO/GSE107451
  • GEO/GSE142789