Antara Rao, Nuo Chen, Min Joo Kim, Jessica Blumenfeld, Oscar Yip, Zherui Liang, David Shostak, Yanxia Hao, Maxine R. Nelson, Nicole Koutsodendris, Brian Grone, Leo Ding, Seo Yeon Yoon, Patrick Arriola, Misha Zilberter, Yadong Huang
{"title":"在嵌合型阿尔茨海默病模型中,消耗小胶质细胞可减少人类神经元与 APOE4 相关的病变","authors":"Antara Rao, Nuo Chen, Min Joo Kim, Jessica Blumenfeld, Oscar Yip, Zherui Liang, David Shostak, Yanxia Hao, Maxine R. Nelson, Nicole Koutsodendris, Brian Grone, Leo Ding, Seo Yeon Yoon, Patrick Arriola, Misha Zilberter, Yadong Huang","doi":"10.1016/j.stem.2024.10.005","DOIUrl":null,"url":null,"abstract":"Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer’s disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived human neurons into the hippocampus of human APOE3 or APOE4 knockin mice and then depleted microglia in half of the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA sequencing analysis identified two pro-inflammatory microglial subtypes with elevated MHC-II gene expression enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"68 1","pages":""},"PeriodicalIF":19.8000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model\",\"authors\":\"Antara Rao, Nuo Chen, Min Joo Kim, Jessica Blumenfeld, Oscar Yip, Zherui Liang, David Shostak, Yanxia Hao, Maxine R. Nelson, Nicole Koutsodendris, Brian Grone, Leo Ding, Seo Yeon Yoon, Patrick Arriola, Misha Zilberter, Yadong Huang\",\"doi\":\"10.1016/j.stem.2024.10.005\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer’s disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived human neurons into the hippocampus of human APOE3 or APOE4 knockin mice and then depleted microglia in half of the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA sequencing analysis identified two pro-inflammatory microglial subtypes with elevated MHC-II gene expression enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.\",\"PeriodicalId\":9665,\"journal\":{\"name\":\"Cell stem cell\",\"volume\":\"68 1\",\"pages\":\"\"},\"PeriodicalIF\":19.8000,\"publicationDate\":\"2024-11-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell stem cell\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.stem.2024.10.005\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell stem cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.stem.2024.10.005","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model
Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer’s disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived human neurons into the hippocampus of human APOE3 or APOE4 knockin mice and then depleted microglia in half of the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA sequencing analysis identified two pro-inflammatory microglial subtypes with elevated MHC-II gene expression enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.
期刊介绍:
Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.