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Updated: Jul 15, 2025
Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated
Xianwei Wang1, Lu Liu1, Xiaohua Jiang1
1Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad Street, Philadelphia, USA.
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.
Insights
Hyperhomocysteinemia impairs microglial amyloid-beta clearance in Alzheimer's disease. This study identifies key genes involved in this microglial dysfunction, suggesting hypomethylation plays a role.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Hyperhomocysteinemia (HHcy) is linked to Alzheimer's disease (AD) and amyloid-beta (Aβ) accumulation.
- Microglia (MG) dysfunction exacerbates AD, but HHcy's impact on MG Aβ phagocytosis is unknown.
Approach:
- Analyzed microglial transcriptomes from HHcy mice (Cbs-/-) and human/mouse AD datasets.
- Performed meta-analysis integrating MG Aβ phagocytosis models, AD methylomes, and GWAS data.
- Identified differentially expressed genes (DEGs) and key pathways in HHcy and AD microglia.
Key Points:
- HHcy and hypomethylation were observed in Cbs-/- mice, with suppressed phagosome and integrin signaling in their microglia.
- Identified compensatory Aβ phagocytosis activation signatures in human and mouse AD microglia, alongside impaired phagocytosis in human AD microglia.
- Discovered 5 HHcy-suppressed phagocytic AD MG DEGs (Flt1, Calponin 3, Igf1, Cacna2d4, Celsr) regulating microglial migration and Aβ uptake.
Conclusions:
- Established molecular signatures for microglial Aβ phagocytosis response in AD.
- Hypomethylation may modulate HHcy-impaired microglial Aβ phagocytosis in Alzheimer's disease.
