Proliferating microglia exhibit unique transcriptional and functional alterations in Alzheimer’s disease

Proliferation of microglia represents a physiologically process which is accelerated in several neurodegenerative disorders including Alzheimer disease. The effect of such neurodegeneration-associated microglial proliferation on function and disease progression remains unclear. We hypothesized that microglial proliferation into a neurodegenerative environment generates subpopulations displaying transcriptional and functional changes that may contribute to the transition from acute to chronic neuroinflammation. Here, we show that proliferation results in profound alterations of cellular function by providing evidence that newly proliferated microglia show impaired beta-amyloid clearance in vivo. Through sorting of proliferating microglia of APP/PS1 mice and subsequent transcriptome analysis, we define unique proliferation-associated transcriptomic signatures that change with age and beta-amyloid accumulation and are characterized by an enrichment of immune system-related pathways. mRNA sequencing and analysis of proliferating (Ki67+) and non-proliferating (Ki67-) microglia from WT and APP/PS1 mice at 4, 6 and 12 months of age