Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer's disease

We have utilized a single nucleus sequencing approach using 10x Genomics snRNA-seq to understand the role of PU.1 expression level in the determination of microglia activation states relavent to Alzheimer's disease. Microglia have been shown to have both neuroprotective and neurotoxic functions during disease, however it remains to be understood how these states are regulated. This study provides new insights into the protective function of microglia mediated by a transcriptional shift toward lymphoid gene expression. Lineage traced microglia nuclei (Cx3cr1CreErt2/+(Litt);Eef1a1LSL.eGFPL10a/+) from 5xFAD, 5xFAD; PU.1-low, 5xFAD; PU.1-high, and 5xFAD with CSF1R inhbition were sorted using fluorescence-activated nucleus sorting (FANS) and analyzed using snRNA-seq.