Distinct Transposable Element Transcript Patterns in Microglia Across Aging and Alzheimer's Disease

ABSTRACT

Microglia, the brain's resident immune cells, are transcriptionally diverse and highly dynamic, but during aging and disease they lose their transcriptomic flexibility and adopt a chronically activated state that is associated with neuroinflammation and pathology. An emerging transcriptomic process that is also increasingly implicated in brain aging, neuroinflammation, and disease is the dysregulation of transposable elements (TEs), repetitive genomic sequences with the potential to cause cellular stress/dysfunction. However, there are limited data on microglial TE transcript patterns in these contexts. Here, we analyzed multiple RNA‐seq datasets from isolated human and mouse microglia across aging, Alzheimer's disease (AD), and AD‐associated pathology. In contrast to previous observations based on whole‐brain tissue and other brain cell types, we found that microglial TE transcript levels remained relatively consistent throughout most of the human lifespan before increasing in late life. We also found that TE transcript levels in microglia from AD patients showed minimal changes compared to age‐matched controls, and in RNA‐seq analyses of transgenic AD mouse models we observed pathology‐associated TE transcript decreases. Subsequent analyses identified inverse associations between TE transcript levels and autophagy/lysosome‐related gene expression, and in vitro studies suggested that aging‐ and AD‐relevant stimuli, as well as pharmacological autophagy inhibition, modulate TE transcript expression in cultured human microglia. Together, these data provide novel insight into TE transcript dynamics in microglia, highlighting TE transcript patterns that differ from those observed in whole‐brain samples and other cell types in aging and AD.