Tau polarizes an aging transcriptional signature to excitatory neurons and glia

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.

Automated summary

Aging is a major risk factor for Alzheimer's disease, and cell-type vulnerability plays a crucial role in its clinical manifestations. The study found that tau protein-induced changes in gene expression are mainly concentrated in excitatory neurons and glia cells and can activate or suppress innate immune gene expression in a cell-type-specific manner. Furthermore, the research also highlights the conservation of cell-type-specific transcriptional patterns between fruit flies and human brain tissue.