scRNA-seq of cerebral organoids to elucidate APP promotes Alzheimer's disease through impairing SIGMAR1 function
We established cerebral organoids derived from human embryonic stem cells and induced pluripotent stem cells carrying Alzheimer's disease-associated mutations to investigate causal mechanisms underlying AD initiation and progression. Through single-cell RNA sequencing and proteomic profiling of individual organoids, combined with clinical single-cell RNA sequencing data from human AD brains, we systematically identified key regulatory nodes in AD, among which SIGMAR1 emerged as a top candidate. Using the APEX2-ACUMEN technique under AD pathological conditions, we mapped the SIGMAR1 interactome and identified APP as a key interacting partner. We further demonstrated that APP pathology leads to impaired SIGMAR1 function across multiple AD models, including 3×Tg primary neurons, 5×FAD mice, and cerebral organoids. Though a high-content compound screening, we found that ipragliflozin effectively blocks APP-SIGMAR1 interaction and alleviates AD pathology in both cerebral organoids and animal models. Our findings provide novel insights into AD pathogenesis and offer therapeutic strategies targeting the APP-SIGMAR1 axis.
We established cerebral organoids derived from human embryonic stem cells and induced pluripotent stem cells carrying Alzheimer's disease-associated mutations to investigate causal mechanisms underlying AD initiation and progression. Through single-cell RNA sequencing and proteomic profiling of individual organoids, combined with clinical single-cell RNA sequencing data from human AD brains, we systematically identified key regulatory nodes in AD, among which SIGMAR1 emerged as a top candidate. Using the APEX2-ACUMEN technique under AD pathological conditions, we mapped the SIGMAR1 interactome and identified APP as a key interacting partner. We further demonstrated that APP pathology leads to impaired SIGMAR1 function across multiple AD models, including 3×Tg primary neurons, 5×FAD mice, and cerebral organoids. Though a high-content compound screening, we found that ipragliflozin effectively blocks APP-SIGMAR1 interaction and alleviates AD pathology in both cerebral organoids and animal models. Our findings provide novel insights into AD pathogenesis and offer therapeutic strategies targeting the APP-SIGMAR1 axis.
Westlake university