PMID- 37789414
OWN - NLM
STAT- MEDLINE
DCOM- 20231005
LR  - 20231123
IS  - 1758-9193 (Electronic)
VI  - 15
IP  - 1
DP  - 2023 Oct 3
TI  - Identification of methylation-regulated genes modulating microglial phagocytosis 
      in hyperhomocysteinemia-exacerbated Alzheimer's disease.
PG  - 164
LID - 10.1186/s13195-023-01311-9 [doi]
LID - 164
AB  - BACKGROUND: Hyperhomocysteinemia (HHcy) has been linked to development of 
      Alzheimer's disease (AD) neuropathologically characterized by the accumulation of 
      amyloid beta (Abeta). Microglia (MG) play a crucial role in uptake of Abeta fibrils, and 
      its dysfunction worsens AD. However, the effect of HHcy on MG Abeta phagocytosis 
      remains unstudied. METHODS: We isolated MG from the cerebrum of HHcy mice with 
      genetic cystathionine-beta-synthase deficiency (Cbs(-/-)) and performed bulk 
      RNA-seq. We performed meta-analysis over transcriptomes of Cbs(-/-) mouse MG, 
      human and mouse AD MG, MG Abeta 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 Abeta phagocytosis model, we identified 130 
      functional-validated Abeta phagocytic AD MG DEGs (20 in human AD, 110 in mouse AD), 
      which reflected a compensatory activation of Abeta phagocytosis. Interestingly, we 
      identified 14 human Abeta phagocytic AD MG DEGs which represented impaired MG Abeta 
      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/MPhi 
      migration and Abeta phagocytosis. CONCLUSIONS: We established molecular signatures 
      for a compensatory response of Abeta phagocytosis activation in human and mouse AD 
      MG and impaired Abeta phagocytosis in human AD MG. Our discoveries suggested that 
      hypomethylation may modulate HHcy-suppressed MG Abeta phagocytosis in AD.
CI  - (c) 2023. BioMed Central Ltd., part of Springer Nature.
FAU - Wang, Xianwei
AU  - Wang X
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Liu, Lu
AU  - Liu L
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Jiang, Xiaohua
AU  - Jiang X
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Saredy, Jason
AU  - Saredy J
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Xi, Hang
AU  - Xi H
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Cueto, Ramon
AU  - Cueto R
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Sigler, Danni
AU  - Sigler D
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Khan, Mohsin
AU  - Khan M
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Wu, Sheng
AU  - Wu S
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Ji, Yong
AU  - Ji Y
AD  - Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing 
      Medical University, Nanjing, 211166, Jiangsu, China.
FAU - Snyder, Nathaniel W
AU  - Snyder NW
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Hu, Wenhui
AU  - Hu W
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Yang, Xiaofeng
AU  - Yang X
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA.
FAU - Wang, Hong
AU  - Wang H
AD  - Center for Metabolic Disease Research, Department of Cardiovascular Science, 
      Lewis Kats School of Medicine, Temple University, MERB, Room 1060, 3500 N. Broad 
      Street, Philadelphia, USA. hongw@temple.edu.
LA  - eng
GR  - R01 DK113775/DK/NIDDK NIH HHS/United States
GR  - DK113775/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, N.I.H., Extramural
DEP - 20231003
PL  - England
TA  - Alzheimers Res Ther
JT  - Alzheimer's research & therapy
JID - 101511643
RN  - 0 (Amyloid beta-Peptides)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Humans
MH  - *Alzheimer Disease/metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - Microglia/metabolism
MH  - *Hyperhomocysteinemia/complications/genetics/metabolism
MH  - Methylation
MH  - Phagocytosis
MH  - Disease Models, Animal
MH  - Mice, Transgenic
PMC - PMC10546779
OTO - NOTNLM
OT  - Alzheimer's
OT  - Amyloid beta
OT  - Hyperhomocysteinemia
OT  - Hypomethylation
OT  - Microglia
OT  - Phagocytosis
COIS- The authors declare no competing interests.
EDAT- 2023/10/04 00:42
MHDA- 2023/10/05 06:43
PMCR- 2023/10/03
CRDT- 2023/10/03 23:53
PHST- 2023/08/10 00:00 [received]
PHST- 2023/09/20 00:00 [accepted]
PHST- 2023/10/05 06:43 [medline]
PHST- 2023/10/04 00:42 [pubmed]
PHST- 2023/10/03 23:53 [entrez]
PHST- 2023/10/03 00:00 [pmc-release]
AID - 10.1186/s13195-023-01311-9 [pii]
AID - 1311 [pii]
AID - 10.1186/s13195-023-01311-9 [doi]
PST - epublish
SO  - Alzheimers Res Ther. 2023 Oct 3;15(1):164. doi: 10.1186/s13195-023-01311-9.