Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation

SUMMARY

Damage-associated microglia (DAM) profiles observed in Alzheimer’s disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease.

In Brief

Gene expression analysis of human AD microglia has been limited by technical challenges. Srinivasan et al. use RNA-seq to profile FACS-purified microglia from frozen AD and control brains, revealing that human AD microglia exhibit accelerated aging, as well as age-independent changes, like upregulation of APOE.

Graphical Abstract