Microglial transcriptional profiles of a transgenic rat model closely model Alzheimer's disease
Carrie J Finno1, Sharmila Ghosh1, Veronika Rodriguez1
1Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA.
Abstract:
Single-cell RNA-sequencing has identified that Alzheimer's disease (AD) pathology in humans is associated with activation of disease-associated microglia (DAM). Microglial signatures of human AD have not been consistently identified in AD mouse models. Since the inflammatory response of rats is more like humans, we profiled microglial transcriptomes in aging TgF344-AD rats, which overexpress two human AD risk genes. Classic DAM gene activation (ApoE, Trem2, Gpnmb), and upregulation (MHC class-II) and downregulation (Ifngr1 and Fkbp5) of human AD microglial genes were identified in aging TgF344-AD rats. Thus, the TgF344-AD rat better recapitulates the microglial gene signature observed in human AD.
Insights
Alzheimer's disease (AD) pathology involves activated microglia. Aging TgF344-AD rats show similar microglial gene changes as human AD, making them a better model for studying AD-associated microglia.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Single-cell RNA-sequencing reveals Alzheimer's disease (AD) pathology is linked to activated disease-associated microglia (DAM) in humans.
- Existing AD mouse models often fail to consistently replicate human AD-associated microglial gene expression patterns.
Purpose of the Study:
- To investigate whether aging TgF344-AD rats, which overexpress human AD risk genes, better recapitulate the microglial gene signature observed in human AD.
- To profile microglial transcriptomes in aging TgF344-AD rats, leveraging their inflammatory response similarity to humans.
Main Methods:
- Transcriptomic profiling of microglia from aging TgF344-AD rats.
- Comparison of identified microglial gene signatures with those reported in human AD.
Main Results:
- Aging TgF344-AD rats exhibited classic disease-associated microglia (DAM) gene activation, including ApoE, Trem2, and Gpnmb.
- Upregulation of MHC class-II and downregulation of Ifngr1 and Fkbp5 were observed in TgF344-AD rat microglia, mirroring human AD microglial gene changes.
Conclusions:
- The TgF344-AD rat model demonstrates a superior recapitulation of the microglial gene signature associated with human Alzheimer's disease.
- This rat model offers a more relevant platform for studying AD pathogenesis and potential therapeutic targets related to microglial dysfunction.
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