In vivo mouse microglia scRNA seq
To address the question of whether ?-secretase deficiency affects the tonic signaling in microglia in vivo as well, we analyzed the single-cell transcriptomes of the ?-secretase deficient microglia from WT and AD mouse models at 3 ,6 and 7 months of age. Like the in vitro observations, genetic knockout of ?-secretase induced mild changes to the transcriptomes of in vivo microglia in the WT mice and also AD mice at 3 months. However, The relative proportions of DAM, CRM and TRM were significantly reduced in AppNL-G-F-GSi?MG mice compared to AppNL-G-F-GSWT mice at 7 months, whereas HM and tCRM were significantly increased. Thus ?-secretase has a crucial role in the microglial transition from the homeostatic to the full DAM phenotype in AD. Overall design: Mice were treated with tamoxifen or vehicle at 1 month of age and were sacrificed at 3, 6 or 7 months for single-cell transcriptomics analysis. To evaluate the potential effects of tamoxifen, we treated the Aph1-floxed mice (WT background and APPNLGF background) with or without tamoxifen and performed single-cell RNA sequencing to evaluate the transcriptional microglia cell states in these mice. N = 4 mice in each condition.