High throughput identification of genetic regulators of microglial inflammatory processes in Alzheimer's disease DOI Open Access
Christopher L. Cardona, Wei Lai, Joonwon Kim

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Genome-wide association studies (GWAS) have identified over a hundred genetic risk factors for Alzheimer's disease (AD), many of which are predominantly expressed in microglia. However, the pathogenic role most them remains unclear. To systematically investigate how AD GWAS variants influence human microglial inflammatory responses, we conducted CRISPR inhibition (CRISPRi) screens targeting 119 hits hiPSC-derived microglia (iMGLs) and used production reactive oxygen species (ROS) response to viral mimic poly(I:C) as functional readout. Top whose knockdown either increased or decreased ROS levels were further analyzed using CROP-seq integrate CRISPRi with single-cell RNA sequencing (scRNA-seq). This analysis 9 unique clusters, including poly(I:C)-driven cluster 2. Emerging evidence supports infections cross comparison our scRNA-seq data iMGLs xenotransplanted into an mouse model shows significant overlap between clusters AD-relevant clusters. Knockdown MS4A6A EED , resulted elevated presence poly(I:C), proportion 2 cells induced functionally related changes gene expression. In addition, KD MS4A6 led reduction DAM (disease associated microglia) under all conditions, suggesting that this may modulate response. contrast, INPP5D RAPEP1 lead low did not significantly affect but rather shaped included upregulation HLA-associated (cluster 6) by independent stimulation. Importantly, had shared differentially genes (DEGs) both vehicle treated conditions. Overall, findings demonstrate despite diverse biological functions variants, they converge regulate states shape responses relevant pathology.

Язык: Английский

High throughput identification of genetic regulators of microglial inflammatory processes in Alzheimer's disease DOI Open Access
Christopher L. Cardona, Wei Lai, Joonwon Kim

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Genome-wide association studies (GWAS) have identified over a hundred genetic risk factors for Alzheimer's disease (AD), many of which are predominantly expressed in microglia. However, the pathogenic role most them remains unclear. To systematically investigate how AD GWAS variants influence human microglial inflammatory responses, we conducted CRISPR inhibition (CRISPRi) screens targeting 119 hits hiPSC-derived microglia (iMGLs) and used production reactive oxygen species (ROS) response to viral mimic poly(I:C) as functional readout. Top whose knockdown either increased or decreased ROS levels were further analyzed using CROP-seq integrate CRISPRi with single-cell RNA sequencing (scRNA-seq). This analysis 9 unique clusters, including poly(I:C)-driven cluster 2. Emerging evidence supports infections cross comparison our scRNA-seq data iMGLs xenotransplanted into an mouse model shows significant overlap between clusters AD-relevant clusters. Knockdown MS4A6A EED , resulted elevated presence poly(I:C), proportion 2 cells induced functionally related changes gene expression. In addition, KD MS4A6 led reduction DAM (disease associated microglia) under all conditions, suggesting that this may modulate response. contrast, INPP5D RAPEP1 lead low did not significantly affect but rather shaped included upregulation HLA-associated (cluster 6) by independent stimulation. Importantly, had shared differentially genes (DEGs) both vehicle treated conditions. Overall, findings demonstrate despite diverse biological functions variants, they converge regulate states shape responses relevant pathology.

Язык: Английский

Процитировано

0