Huaxi Xu, China
Xiamen University Institute of NeuroscienceAuthor Of 3 Presentations
LIVE DISCUSSION
- Carmen Romero-Molina, Spain
- Sudeshna Das, United States of America
- Sivaprakasam Ramamoorthy, United States of America
- Sigal Fleisher-Berkovich, Israel
- Amitha Muraleedharan, Israel
- Francheska Delgado-Peraza, United States of America
- Malu G. Tansey, United States of America
- Huaxi Xu, China
- Dietmar R. Thal, Belgium
- Bijayani Sahu, United States of America
LIVE DISCUSSION
ROLES FOR MICROGLIAL ALZHEIMER'S RISK GENES IN REGULATION OF BETA-AMYLOID METABOLISM AND MICROGLIA FUNCTION
Abstract
Abstract Body
Microglia are increasingly implicated in age-related Alzheimer's disease (AD). Many late-onset AD-related genes are microglia-specific. However, interplay between the AD-related genes in microglia, Aß metabolism and aging remains largely elusive. Recently, we have established isogenic human ES-derived microglia (hMGLs) harboring AD-associated variants in APOE, TREM2, CD33, INPP5D, and SORL1 loci or knockout (KO) by CRISPR/Cas9 gene editing, and through induced differentiation and subsequent treatments with aged human serum. We carry out multi-omics studies including RNAseq, ATACseq, ChIPseq, and proteomics to systematically evaluate the correlations among aging, Aß metabolism and AD-related genes. Moreover, we functionally characterize hMGLs in vitro and in vivo, such as responses to various physio/pathological stimuli, Aβ phagocytosis, and AD-like phenotypes in AD model mice through xenotransplantation. In our preliminary study, we have established the microglial aging model by adding aged human serum in culture and generated hMGLs harboring the AD-associated TREM2 mutant R47H. AD-like expression signatures were observed in TREM2-R47H hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicated that APOE was a convergent pathogenic node. AD-associated TREM2-R47H can enhance APOE expression and impair hMGLs Aβ uptake in an APOE-dependent manner. Xenotransplants of TREM2-R47H hMGLs reduced Aβ uptake/clearance in the brain of AD mice. Moreover, we found that AD-associated gene expression landscape significantly altered during microglial aging. Our study shall provide new insights into the contribution of microglial aging and the interplay between aging, Aß metabolism and AD genes in microglia to AD pathogenesis, and may identify new strategies for AD therapeutics.
Presenter of 3 Presentations
LIVE DISCUSSION
- Carmen Romero-Molina, Spain
- Sudeshna Das, United States of America
- Sivaprakasam Ramamoorthy, United States of America
- Sigal Fleisher-Berkovich, Israel
- Amitha Muraleedharan, Israel
- Francheska Delgado-Peraza, United States of America
- Malu G. Tansey, United States of America
- Huaxi Xu, China
- Dietmar R. Thal, Belgium
- Bijayani Sahu, United States of America
LIVE DISCUSSION
ROLES FOR MICROGLIAL ALZHEIMER'S RISK GENES IN REGULATION OF BETA-AMYLOID METABOLISM AND MICROGLIA FUNCTION
Abstract
Abstract Body
Microglia are increasingly implicated in age-related Alzheimer's disease (AD). Many late-onset AD-related genes are microglia-specific. However, interplay between the AD-related genes in microglia, Aß metabolism and aging remains largely elusive. Recently, we have established isogenic human ES-derived microglia (hMGLs) harboring AD-associated variants in APOE, TREM2, CD33, INPP5D, and SORL1 loci or knockout (KO) by CRISPR/Cas9 gene editing, and through induced differentiation and subsequent treatments with aged human serum. We carry out multi-omics studies including RNAseq, ATACseq, ChIPseq, and proteomics to systematically evaluate the correlations among aging, Aß metabolism and AD-related genes. Moreover, we functionally characterize hMGLs in vitro and in vivo, such as responses to various physio/pathological stimuli, Aβ phagocytosis, and AD-like phenotypes in AD model mice through xenotransplantation. In our preliminary study, we have established the microglial aging model by adding aged human serum in culture and generated hMGLs harboring the AD-associated TREM2 mutant R47H. AD-like expression signatures were observed in TREM2-R47H hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicated that APOE was a convergent pathogenic node. AD-associated TREM2-R47H can enhance APOE expression and impair hMGLs Aβ uptake in an APOE-dependent manner. Xenotransplants of TREM2-R47H hMGLs reduced Aβ uptake/clearance in the brain of AD mice. Moreover, we found that AD-associated gene expression landscape significantly altered during microglial aging. Our study shall provide new insights into the contribution of microglial aging and the interplay between aging, Aß metabolism and AD genes in microglia to AD pathogenesis, and may identify new strategies for AD therapeutics.