Amyloid-β Seeding in Early Disease Stages: Effects of early-life infection and sex differences on glial cells in Alzheimer’s Disease
(2025) BINP52 20242Degree Projects in Bioinformatics
- Abstract
- Alzheimer's disease (AD) is a neurodegenerative disease that often occurs in the elderly and is often accompanied by cognitive loss. Its main pathological features are the formation of amyloid-beta (Aβ) plaques and Tau tangles in the brain. Here, we used single-cell RNA sequencing (scRNA-seq) combined with computational cell–cell communication (CCC) analysis to systematically investigate transcriptional profiles across astrocytes, microglia, and oligodendrocytes in both wild-type and 5xFAD mice under lipopolysaccharide (LPS) stimulation at early stage of the Aβ pathology (9 weeks of age).
Across different cell types, genotype or treatment alone caused only limited compositional shifts at this early stage, however, by incorporating sex as... (More) - Alzheimer's disease (AD) is a neurodegenerative disease that often occurs in the elderly and is often accompanied by cognitive loss. Its main pathological features are the formation of amyloid-beta (Aβ) plaques and Tau tangles in the brain. Here, we used single-cell RNA sequencing (scRNA-seq) combined with computational cell–cell communication (CCC) analysis to systematically investigate transcriptional profiles across astrocytes, microglia, and oligodendrocytes in both wild-type and 5xFAD mice under lipopolysaccharide (LPS) stimulation at early stage of the Aβ pathology (9 weeks of age).
Across different cell types, genotype or treatment alone caused only limited compositional shifts at this early stage, however, by incorporating sex as a variable revealed robust, sex-dependent differences. Astrocytes (AC) resolved into region-specific populations according to previous knowledge, including hippocampus, glia limitans superficialis (GLS), and white matter, as well as a small GFAP+ subset.
Overall astrocytic proportions were stable across genotypes and treatments, but males showed a more evident depletion of homeostatic clusters after LPS, and a few clusters exhibited strong sex-specific changes. Microglial composition was broadly stable, yet CCC uncovered sex-dependent patterns on microglial activation. Oligodendrocytes (OL) largely retained homeostatic signatures without a disease-associated oligodendrocyte population; nevertheless, OL3 was most LPS-responsive in WT males, OL4/OL5 selectively expanded in LPS-treated 5XFAD females, and OL6 displayed opposite trends between male and female.
Communication analysis identified sex-specific signaling axes. Astrocyte/oligodendrocyte-derived Sema6d-Trem2/Tyrobp predominated in females, whereas males preferentially engaged Gas6-TAM receptors and OL-derived Sema4d-Plxnb1/b2, aligning with transcriptional programs of microglial activation, phagocytosis, and inflammation. Mechanistically, Sema6d–Trem2 signaling was associated with enhanced microglial activation, phagocytosis, and inflammatory responses, potentially contributing to sex-dependent vulnerability in AD.
Collectively, our study reveals sex-divergent glial communication routes, providing new mechanistic insights into AD pathology and highlighting potential targets for sex-tailored therapeutic interventions. (Less) - Popular Abstract
- Alzheimer’s disease is a neurodegenerative brain disorder that gradually impairs memory and thinking. We investigated how genotype and inflammatory treatment shape glial cell states at an early stage of Aβ pathology. To this end, we combined single-cell RNA sequencing with computational cell–cell communication analysis to profile astrocytes, microglia, and oligodendrocytes in wild-type and 5xFAD mice following lipopolysaccharide stimulation at nine weeks of age.
In general, across cell types, astrocytes, microglia, and mature oligodendrocytes largely exhibited homeostatic phenotype profiles, suggesting they are in a standby state to transition into disease-associated states. In addition, astrocytes displayed clear region-specific... (More) - Alzheimer’s disease is a neurodegenerative brain disorder that gradually impairs memory and thinking. We investigated how genotype and inflammatory treatment shape glial cell states at an early stage of Aβ pathology. To this end, we combined single-cell RNA sequencing with computational cell–cell communication analysis to profile astrocytes, microglia, and oligodendrocytes in wild-type and 5xFAD mice following lipopolysaccharide stimulation at nine weeks of age.
In general, across cell types, astrocytes, microglia, and mature oligodendrocytes largely exhibited homeostatic phenotype profiles, suggesting they are in a standby state to transition into disease-associated states. In addition, astrocytes displayed clear region-specific signatures, and certain subclusters of mature oligodendrocytes and astrocytes showed sex-dependent responses.
Communication analysis revealed many contrasts. One of them is, astrocyte- and oligodendrocyte-derived signaling pathways frequently engaged a Sema6d → Trem2/Tyrobp axis, consistent with stronger microglial activation, debris clearance (phagocytosis), and inflammation in females. While in males, signaling interactions preferentially involved Gas6 → TAM receptors and oligodendrocyte-derived Sema4d → Plexin-B1/B2. Recognizing these sex-specific pathways offers new insight into early mechanisms of Alzheimer’s disease and highlights opportunities for sex-tailored therapeutic strategies. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9215051
- author
- Tian, Mi
- supervisor
-
- Yiyi Yang LU
- Tomas Deierborg LU
- organization
- course
- BINP52 20242
- year
- 2025
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9215051
- date added to LUP
- 2025-11-07 10:48:28
- date last changed
- 2025-11-07 10:48:28
@misc{9215051,
abstract = {{Alzheimer's disease (AD) is a neurodegenerative disease that often occurs in the elderly and is often accompanied by cognitive loss. Its main pathological features are the formation of amyloid-beta (Aβ) plaques and Tau tangles in the brain. Here, we used single-cell RNA sequencing (scRNA-seq) combined with computational cell–cell communication (CCC) analysis to systematically investigate transcriptional profiles across astrocytes, microglia, and oligodendrocytes in both wild-type and 5xFAD mice under lipopolysaccharide (LPS) stimulation at early stage of the Aβ pathology (9 weeks of age).
Across different cell types, genotype or treatment alone caused only limited compositional shifts at this early stage, however, by incorporating sex as a variable revealed robust, sex-dependent differences. Astrocytes (AC) resolved into region-specific populations according to previous knowledge, including hippocampus, glia limitans superficialis (GLS), and white matter, as well as a small GFAP+ subset.
Overall astrocytic proportions were stable across genotypes and treatments, but males showed a more evident depletion of homeostatic clusters after LPS, and a few clusters exhibited strong sex-specific changes. Microglial composition was broadly stable, yet CCC uncovered sex-dependent patterns on microglial activation. Oligodendrocytes (OL) largely retained homeostatic signatures without a disease-associated oligodendrocyte population; nevertheless, OL3 was most LPS-responsive in WT males, OL4/OL5 selectively expanded in LPS-treated 5XFAD females, and OL6 displayed opposite trends between male and female.
Communication analysis identified sex-specific signaling axes. Astrocyte/oligodendrocyte-derived Sema6d-Trem2/Tyrobp predominated in females, whereas males preferentially engaged Gas6-TAM receptors and OL-derived Sema4d-Plxnb1/b2, aligning with transcriptional programs of microglial activation, phagocytosis, and inflammation. Mechanistically, Sema6d–Trem2 signaling was associated with enhanced microglial activation, phagocytosis, and inflammatory responses, potentially contributing to sex-dependent vulnerability in AD.
Collectively, our study reveals sex-divergent glial communication routes, providing new mechanistic insights into AD pathology and highlighting potential targets for sex-tailored therapeutic interventions.}},
author = {{Tian, Mi}},
language = {{eng}},
note = {{Student Paper}},
title = {{Amyloid-β Seeding in Early Disease Stages: Effects of early-life infection and sex differences on glial cells in Alzheimer’s Disease}},
year = {{2025}},
}