鉴定甲基化调控基因调节高同型半胱氨酸血症加重阿尔茨海默病中小胶质细胞的吞噬作用。

Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer's disease.

机构信息

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.

Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.

出版信息

Alzheimers Res Ther. 2023 Oct 3;15(1):164. doi: 10.1186/s13195-023-01311-9.

DOI:10.1186/s13195-023-01311-9

PMID:37789414

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10546779/

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.

摘要

背景

高同型半胱氨酸血症（HHcy）与阿尔茨海默病（AD）的病理学发展有关，其特征是淀粉样β（Aβ）的积累。小胶质细胞（MG）在摄取 Aβ 纤维方面起着至关重要的作用，其功能障碍会使 AD 恶化。然而，HHcy 对 MG 摄取 Aβ的影响仍未得到研究。

方法

我们从遗传性胱硫醚-β-合酶缺乏症（Cbs）的 HHcy 小鼠大脑中分离出 MG，并进行了批量 RNA-seq。我们对 Cbs 小鼠 MG、人类和小鼠 AD MG、MG 摄取 Aβ的模型、人类 AD 甲基组和 GWAS AD 基因的转录组进行了荟萃分析。

结果

在 Cbs 小鼠中发现 HHcy 和低甲基化条件。通过 Cbs MG 转录组分析，鉴定出 353 个 MG DEGs。发现 Cbs MG 中的吞噬体形成和整合素信号通路受到抑制。通过分析 4 名 AD 患者和 7 名小鼠 AD 数据集的 MG 转录组，鉴定出 409 个人类和 777 个小鼠 AD MG DEGs，其中 37 个在两个物种中都存在。通过与 MG 摄取 Aβ的模型的转录组进行进一步的组合分析，我们鉴定出 130 个功能验证的 Aβ吞噬性 AD MG DEGs（20 个在人类 AD 中，110 个在小鼠 AD 中），这反映了 Aβ吞噬作用的代偿性激活。有趣的是，我们在人类 AD 中鉴定出 14 个人类 Aβ吞噬性 AD MG DEGs，代表人类 AD 中 MG 摄取 Aβ的受损。最后，通过对 AD MG、功能吞噬、HHcy MG 和人类 AD 大脑甲基组数据集的转录组的级联荟萃分析，我们鉴定出 5 个 HHcy 抑制的吞噬性 AD MG DEGs（Flt1、Calponin 3、Igf1、Cacna2d4 和 Celsr），它们被报道调节 MG/MΦ 迁移和 Aβ 吞噬作用。