Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease
Abstract Background Hyperhomocysteinemia (HHcy) has been linked to development of Alzheimer’s disease (AD) neuropathologically characterized by the accumulation of amyloid β (Aβ). Microglia (MG) play a crucial role in uptake of Aβ fibrils, and its dysfunction worsens AD. However, the effect of HHcy...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-10-01
|
| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-023-01311-9 |
| _version_ | 1827635318574022656 |
|---|---|
| author | Xianwei Wang Lu Liu Xiaohua Jiang Jason Saredy Hang Xi Ramon Cueto Danni Sigler Mohsin Khan Sheng Wu Yong Ji Nathaniel W. Snyder Wenhui Hu Xiaofeng Yang Hong Wang |
| author_facet | Xianwei Wang Lu Liu Xiaohua Jiang Jason Saredy Hang Xi Ramon Cueto Danni Sigler Mohsin Khan Sheng Wu Yong Ji Nathaniel W. Snyder Wenhui Hu Xiaofeng Yang Hong Wang |
| author_sort | Xianwei Wang |
| collection | DOAJ |
| description | Abstract Background Hyperhomocysteinemia (HHcy) has been linked to development of Alzheimer’s disease (AD) neuropathologically characterized by the accumulation of amyloid β (Aβ). Microglia (MG) play a crucial role in uptake of Aβ fibrils, and its dysfunction worsens AD. However, the effect of HHcy on MG Aβ phagocytosis remains unstudied. Methods We isolated MG from the cerebrum of HHcy mice with genetic cystathionine-β-synthase deficiency (Cbs −/− ) and performed bulk RNA-seq. We performed meta-analysis over transcriptomes of Cbs −/− mouse MG, human and mouse AD MG, MG Aβ phagocytosis model, human AD methylome, and GWAS AD genes. Results HHcy and hypomethylation conditions were identified in Cbs −/− mice. Through Cbs −/− MG transcriptome analysis, 353 MG DEGs were identified. Phagosome formation and integrin signaling pathways were found suppressed in Cbs −/− MG. By analyzing MG transcriptomes from 4 AD patient and 7 mouse AD datasets, 409 human and 777 mouse AD MG DEGs were identified, of which 37 were found common in both species. Through further combinatory analysis with transcriptome from MG Aβ phagocytosis model, we identified 130 functional-validated Aβ phagocytic AD MG DEGs (20 in human AD, 110 in mouse AD), which reflected a compensatory activation of Aβ phagocytosis. Interestingly, we identified 14 human Aβ phagocytic AD MG DEGs which represented impaired MG Aβ phagocytosis in human AD. Finally, through a cascade of meta-analysis of transcriptome of AD MG, functional phagocytosis, HHcy MG, and human AD brain methylome dataset, we identified 5 HHcy-suppressed phagocytic AD MG DEGs (Flt1, Calponin 3, Igf1, Cacna2d4, and Celsr) which were reported to regulate MG/MΦ migration and Aβ phagocytosis. Conclusions We established molecular signatures for a compensatory response of Aβ phagocytosis activation in human and mouse AD MG and impaired Aβ phagocytosis in human AD MG. Our discoveries suggested that hypomethylation may modulate HHcy-suppressed MG Aβ phagocytosis in AD. |
| first_indexed | 2024-03-09T15:25:08Z |
| format | Article |
| id | doaj.art-2f25920bcdce4d459ea752eb0ce81137 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-03-09T15:25:08Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-2f25920bcdce4d459ea752eb0ce811372023-11-26T12:32:52ZengBMCAlzheimer’s Research & Therapy1758-91932023-10-0115111710.1186/s13195-023-01311-9Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s diseaseXianwei Wang0Lu Liu1Xiaohua Jiang2Jason Saredy3Hang Xi4Ramon Cueto5Danni Sigler6Mohsin Khan7Sheng Wu8Yong Ji9Nathaniel W. Snyder10Wenhui Hu11Xiaofeng Yang12Hong Wang13Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityKey Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityCenter for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple UniversityAbstract Background Hyperhomocysteinemia (HHcy) has been linked to development of Alzheimer’s disease (AD) neuropathologically characterized by the accumulation of amyloid β (Aβ). Microglia (MG) play a crucial role in uptake of Aβ fibrils, and its dysfunction worsens AD. However, the effect of HHcy on MG Aβ phagocytosis remains unstudied. Methods We isolated MG from the cerebrum of HHcy mice with genetic cystathionine-β-synthase deficiency (Cbs −/− ) and performed bulk RNA-seq. We performed meta-analysis over transcriptomes of Cbs −/− mouse MG, human and mouse AD MG, MG Aβ phagocytosis model, human AD methylome, and GWAS AD genes. Results HHcy and hypomethylation conditions were identified in Cbs −/− mice. Through Cbs −/− MG transcriptome analysis, 353 MG DEGs were identified. Phagosome formation and integrin signaling pathways were found suppressed in Cbs −/− MG. By analyzing MG transcriptomes from 4 AD patient and 7 mouse AD datasets, 409 human and 777 mouse AD MG DEGs were identified, of which 37 were found common in both species. Through further combinatory analysis with transcriptome from MG Aβ phagocytosis model, we identified 130 functional-validated Aβ phagocytic AD MG DEGs (20 in human AD, 110 in mouse AD), which reflected a compensatory activation of Aβ phagocytosis. Interestingly, we identified 14 human Aβ phagocytic AD MG DEGs which represented impaired MG Aβ phagocytosis in human AD. Finally, through a cascade of meta-analysis of transcriptome of AD MG, functional phagocytosis, HHcy MG, and human AD brain methylome dataset, we identified 5 HHcy-suppressed phagocytic AD MG DEGs (Flt1, Calponin 3, Igf1, Cacna2d4, and Celsr) which were reported to regulate MG/MΦ migration and Aβ phagocytosis. Conclusions We established molecular signatures for a compensatory response of Aβ phagocytosis activation in human and mouse AD MG and impaired Aβ phagocytosis in human AD MG. Our discoveries suggested that hypomethylation may modulate HHcy-suppressed MG Aβ phagocytosis in AD.https://doi.org/10.1186/s13195-023-01311-9Alzheimer’sHyperhomocysteinemiaMicrogliaPhagocytosisHypomethylationAmyloid β |
| spellingShingle | Xianwei Wang Lu Liu Xiaohua Jiang Jason Saredy Hang Xi Ramon Cueto Danni Sigler Mohsin Khan Sheng Wu Yong Ji Nathaniel W. Snyder Wenhui Hu Xiaofeng Yang Hong Wang Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease Alzheimer’s Research & Therapy Alzheimer’s Hyperhomocysteinemia Microglia Phagocytosis Hypomethylation Amyloid β |
| title | Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease |
| title_full | Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease |
| title_fullStr | Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease |
| title_full_unstemmed | Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease |
| title_short | Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease |
| title_sort | identification of methylation regulated genes modulating microglial phagocytosis in hyperhomocysteinemia exacerbated alzheimer s disease |
| topic | Alzheimer’s Hyperhomocysteinemia Microglia Phagocytosis Hypomethylation Amyloid β |
| url | https://doi.org/10.1186/s13195-023-01311-9 |
| work_keys_str_mv | AT xianweiwang identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT luliu identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT xiaohuajiang identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT jasonsaredy identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT hangxi identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT ramoncueto identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT dannisigler identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT mohsinkhan identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT shengwu identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT yongji identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT nathanielwsnyder identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT wenhuihu identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT xiaofengyang identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease AT hongwang identificationofmethylationregulatedgenesmodulatingmicroglialphagocytosisinhyperhomocysteinemiaexacerbatedalzheimersdisease |