Impact of Early-Life Inflammation and APOE Genotype on the Microglial Multi-Omic Profile During Alzheimer’s Disease Pathology
(2025) BINP52 20242Degree Projects in Bioinformatics
- Abstract
- Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaque deposition, tau pathology, and neuroinflammation, with genetic variants in the apolipoprotein E (APOE) gene representing the strongest risk factor for late-onset AD. Microglia, the brain’s resident immune cells, are increasingly recognized as central to disease progression through their roles in neuroinflammation and Aβ clearance. In this study, we investigated how APOE genotype (E3 vs E4) and early-life inflammation interact to shape microglial states in a mouse model of Aβ pathology. Using single-cell RNA sequencing (scRNA-seq) of microglia isolated from APOE3/4 knock-in crossed with 5xFAD (E3FAD/E4FAD) mice treated with lipopolysaccharide (LPS) or vehicle at postnatal... (More)
- Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaque deposition, tau pathology, and neuroinflammation, with genetic variants in the apolipoprotein E (APOE) gene representing the strongest risk factor for late-onset AD. Microglia, the brain’s resident immune cells, are increasingly recognized as central to disease progression through their roles in neuroinflammation and Aβ clearance. In this study, we investigated how APOE genotype (E3 vs E4) and early-life inflammation interact to shape microglial states in a mouse model of Aβ pathology. Using single-cell RNA sequencing (scRNA-seq) of microglia isolated from APOE3/4 knock-in crossed with 5xFAD (E3FAD/E4FAD) mice treated with lipopolysaccharide (LPS) or vehicle at postnatal day 9, we identified distinct microglial transcriptional states and assessed their proportions and gene expression profiles. Female E4FAD mice exhibited a higher proportion of disease-associated microglia (DAM) compared to Female E3FAD mice. Moreover, early-life inflammation induced long-lasting, genotype-specific alterations: LPS reduced the abundance of an NF-κB-enriched Cytokine Response microglial transcriptional state and downregulated pro-inflammatory genes in E4FAD, but not E3FAD, mice. These findings suggest that early-life immune events interact with APOE genotype to shape microglial responses to amyloid pathology and may offer targets for modulating disease-associated inflammation. (Less)
- Popular Abstract
- Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia. In addition to the well-known build-up of amyloid plaques and tau tangles, the brain’s immune system, particularly microglia, is now recognized as a key player in disease progression. Microglia help maintain brain health but can also contribute to damage when chronically activated. A person’s genetic background, especially their APOE genotype, strongly influences how these immune cells behave. The APOE4 variant, in particular, increases the risk of developing Alzheimer’s and is associated with more pronounced brain inflammation.
In this project, I examined how early-life immune challenges interact with APOE genotype to shape microglial... (More) - Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia. In addition to the well-known build-up of amyloid plaques and tau tangles, the brain’s immune system, particularly microglia, is now recognized as a key player in disease progression. Microglia help maintain brain health but can also contribute to damage when chronically activated. A person’s genetic background, especially their APOE genotype, strongly influences how these immune cells behave. The APOE4 variant, in particular, increases the risk of developing Alzheimer’s and is associated with more pronounced brain inflammation.
In this project, I examined how early-life immune challenges interact with APOE genotype to shape microglial responses later in life. Using a well-established mouse model of Alzheimer’s disease, I combined single-cell RNA sequencing and proteomics to analyze microglia at both the gene and protein level. The results showed that early-life inflammation led to long-lasting, APOE4-specific changes in microglial states, particularly reducing the abundance of a subset of cells involved in inflammatory responses. These effects were specific to mice carrying the APOE4 gene and did not occur in those with the APOE3 variant.
These findings show that the long-term effects of early immune events on the brain’s immune system depend on APOE genotype, offering new insight into why individuals with APOE4 may respond differently to inflammation over their lifespan. By demonstrating that early-life experiences can leave a lasting mark on microglial behavior in the context of Alzheimer’s pathology, this work highlights the complex interplay between genetics and environment in shaping disease risk. Understanding these interactions is essential for developing more targeted approaches to prevent Alzheimer’s. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9212612
- author
- Larham, Logan
- supervisor
-
- Tomas Deierborg LU
- Yiyi Yang LU
- organization
- course
- BINP52 20242
- year
- 2025
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9212612
- date added to LUP
- 2025-09-17 16:48:17
- date last changed
- 2025-09-17 16:48:17
@misc{9212612,
abstract = {{Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaque deposition, tau pathology, and neuroinflammation, with genetic variants in the apolipoprotein E (APOE) gene representing the strongest risk factor for late-onset AD. Microglia, the brain’s resident immune cells, are increasingly recognized as central to disease progression through their roles in neuroinflammation and Aβ clearance. In this study, we investigated how APOE genotype (E3 vs E4) and early-life inflammation interact to shape microglial states in a mouse model of Aβ pathology. Using single-cell RNA sequencing (scRNA-seq) of microglia isolated from APOE3/4 knock-in crossed with 5xFAD (E3FAD/E4FAD) mice treated with lipopolysaccharide (LPS) or vehicle at postnatal day 9, we identified distinct microglial transcriptional states and assessed their proportions and gene expression profiles. Female E4FAD mice exhibited a higher proportion of disease-associated microglia (DAM) compared to Female E3FAD mice. Moreover, early-life inflammation induced long-lasting, genotype-specific alterations: LPS reduced the abundance of an NF-κB-enriched Cytokine Response microglial transcriptional state and downregulated pro-inflammatory genes in E4FAD, but not E3FAD, mice. These findings suggest that early-life immune events interact with APOE genotype to shape microglial responses to amyloid pathology and may offer targets for modulating disease-associated inflammation.}},
author = {{Larham, Logan}},
language = {{eng}},
note = {{Student Paper}},
title = {{Impact of Early-Life Inflammation and APOE Genotype on the Microglial Multi-Omic Profile During Alzheimer’s Disease Pathology}},
year = {{2025}},
}