Comparative profiling of hippocampal gene expression in AppNL-G-F knock-in mouse model of Alzheimer's disease.
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ABSTRACT:
PROVIDER: PRJNA660344 | ENA |
REPOSITORIES: ENA
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Project description:Oligodendrocytes provide myelination and metabolic support to neurons, but their contribution to Alzheimer's disease (AD) progression remains incompletely understood. To investigate the molecular effects of oligodendrocyte-specific Fus deletion, we performed single-cell RNA sequencing of hippocampal cells from AppNL-G-F (AD), AppNL-G-F/ Fusfl/fl/Cnpcre/+ (AD/cKO), Fusfl/fl/Cnpcre/+ (cKO), and Fusfl/fl (WT) mice. This dataset defines cell type-specific transcriptional profiles of hippocampal cells and identifies transcriptional changes associated with oligodendrocyte-specific Fus deletion in the context of Alzheimer's disease. These data provide a resource for investigating molecular pathways underlying oligodendrocyte function, glial interactions, and Alzheimer's disease pathogenesis.
2026-07-22 | GSE339460 | GEO
Project description:To identify molecular pathological alterations in Alzheimer’s disease (AD) brains, we had previously performed comparative gene expression profiling with human gene array using RNAs prepared from postmortem human brains donated for the Hisayama study. The hippocampi from AD brains showed the most significant alteration in gene expression profile (PMID: 23595620). In the present study, in order to obtain a comprehensive view of gene expression profiles in AD hippocampus, we applied human transcriptome array and deep RNA-sequencing to the same samples and reanalyzed the gene array data, and performed integrative analysis of all 3 methods. We also applied gene array to hippocampus of 6-month-old App[NL-G-F/NL-G-F] knock-in AD model mice, and at last we performed the interspecies comparison. IPA analysis of the top significantly altered genes derived from integrative analysis of all 3 methods in human AD hippocampus revealed that neurotransmission, synaptic transmission and development of neurons are the top significantly decreased functions. In hippocampi of App[NL-G-F/NL-G-F] mice which exhibit significant amyloidosis but not neuronal degeneration, we found that expression of Gfap (astrocyte marker) and Cd68 (microglia marker) genes are significantly upregulated together with genes categorized in the immune response of cells. Comparing the human and mouse data, we found major common genes are related to recruitment of inflammatory cells. Amyloid-beta accumulation is the major hallmark of AD at 6 month-old App[NL-G-F/NL-G-F] mice, therefore our data suggests that amyloid-beta accumulation increases the recruitment of inflammatory cells in early stage of AD brain, prior to neuronal degeneration.
2021-12-01 | GSE157161 | GEO
Project description:Background Alzheimer's disease (AD) is intricately linked with neuroinflammation, with the complement system, particularly C3, emerging as a critical player. However, research has been hampered by the reliance on classical germline C3 knockout and APP overexpressing mouse models, which do not allow to study temporal and cell-specific C3 effects, and do not accurately reflect the complexity of AD pathology. Methods In this study, we investigated the impact of conditional C3 deficiency on neuroinflammation and AD pathology, by generating microglia-specific (C3mKO), astrocyte-specific (C3aKO), and inducible full-body (C3iKO) C3 knockout mice. To assess the role of C3 in both acute and chronic neuroinflammation, we employed an intracerebroventricular (ICV) LPS injection model in these mice alongside studies in the AppNL-G-F knock-in mouse model of AD upon aging and mild peripheral inflammation. Results Our results show that complement genes, including C3, are upregulated in microglia and astrocytes from 40 weeks old AppNL-G-F mice compared to their wildtype counterparts. Both microglia and astrocytes were shown to be significant sources of C3, as conditional C3 deficiency in either cell type led to decreased C3 expression and a dampened neuroinflammatory transcriptional response following ICV LPS injection. However, microglial- and astrocytic-specific C3 deficiency in AppNL-G-F mice did not affect total hippocampal C3 protein levels and amyloid plaque burden upon both 40 weeks of aging and in mild peripheral inflammation conditions. Also full-body C3 knockout, induced at the age of 8 weeks, did not alter Aβ pathology and glial activation, despite the complete removal of C3. Conclusions Our findings show that while C3 contributes to neuroinflammatory responses, its role in chronic AD-associated pathology is more complex than previously thought. Our study using novel cell-specific and inducible C3 knockout mice combined with the knock-in AppNL-G-F model provides new insights into the cell-specific roles of complement in AD, and highlights the need for further investigation into the complement system's involvement in neurodegenerative diseases.
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Project description:Aim of this experiment was to characterize whether SPP1 released from the hippocampal perivascular space could imprint microglia transcriptional states. We performed scRNA-seq analysis on sorted CD140a+ perivascular fibroblast (PVF), CD45highCD11intCD206+ perivascular macrophage (PVM) and CD45intCD11intCX3CR1high microglial cell from dissected hippocampi of 6-month old wild type vs SPP1KO/KO vs AppNL-F mice vs AppNL-FxSpp1KO/KO mice. Cells were isolated from dissected hippocampi as previously described (Sala Frigerio et al.,2019).
2024-02-09 | E-MTAB-11918 | biostudies-arrayexpress
Project description: Not available
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Project description:In Alzheimer’s disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment. Hippocampal hyperactivity and decreased sleep quality are associated with early AD, but their basis is poorly understood. We find that homeostatic mechanisms transiently counteract increased excitatory drive of hippocampal CA1 neurons in AppNL-G-F mice, but fail to stabilize it at control levels. Spatial transcriptomics (ST) analysis identifies the Pmch gene encoding Melanin-Concentrating Hormone (MCH) as part of the adaptive response in AppNL-G-F mice. Hypothalamic MCH peptide is produced in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission and modulates firing rate homeostasis in hippocampal neurons. Moreover, MCH reverses the increased excitatory drive of CA1 neurons in AppNL-G-F mice. Consistent with our finding that a reduced fraction of MCH-neurons is active in AppNL-G-F mice, these animals spend less time in rapid eye movement (REM) sleep. In addition, MCH-axons projecting to CA1 become progressively impaired in both AppNL-G-F mice and AD patients. Our findings identify the MCH-system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampal-dependent functions.
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Project description:Detecting and understanding Alzheimer's disease (AD) in its early stages is essential for uncovering the initial mechanisms behind its neuropathology and devising effective interventions. In this study, we leveraged the humanized AppNL-G-F mouse which exhibits early-onset amyloid pathology along a predictable timeline, to investigate molecular changes in the hippocampus and blood before the onset of severe neuropathology and independent of aging. Employing a multi-omics approach, we identified alterations in chromatin accessibility, gene expression, and DNA methylation associated with early amyloidosis. Chromatin accessibility changes were prominent in excitatory neurons during early pathology, with a later shift to inhibitory neurons, potentially reflecting compensatory mechanisms to mitigate excitatory neuron dysregulation. Despite broadly comparable hippocampal cell composition, transcriptomic comparisons between wild-type and AppNL-G-F mice revealed major gene expression differences, particularly in pathways related to mitochondrial function and protein biosynthesis, preceding severe amyloid plaque deposition. In later stages, upregulation of immune and neuroinflammatory pathways was observed, aligning with established neuroinflammatory processes in AD. Additionally, we identified extensive DNA methylation differences in both the blood and hippocampus of AppNL-G-F mice during early and late stages of pathology. Many differentially methylated regions in the blood, even at early pathology stages, were associated with cis-regulatory elements in the brain and were located near differentially expressed genes in the hippocampus. These regions were enriched in pathways related to brain function, such as neuron development and synaptic processes, indicating a link between blood methylation patterns and brain function. This suggests the potential utility of blood methylation as a biomarker for early amyloidosis detection. Notably, we identified five candidate biomarker genes, including Rbfox1 and Camta1, with epigenetic dysregulation detectable in both the brain and blood prior to severe amyloid accumulation. Our study, leveraging a unique AD mouse model and a multi-omics approach, highlights epigenetic signatures of AD before the onset of clinical symptoms, providing a foundation for future research into early diagnosis and therapeutic strategies, as well as potential biomarkers.
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Project description:Detecting and understanding Alzheimer's disease (AD) in its early stages is essential for uncovering the initial mechanisms behind its neuropathology and devising effective interventions. In this study, we leveraged the humanized AppNL-G-F mouse which exhibits early-onset amyloid pathology along a predictable timeline, to investigate molecular changes in the hippocampus and blood before the onset of severe neuropathology and independent of aging. Employing a multi-omics approach, we identified alterations in chromatin accessibility, gene expression, and DNA methylation associated with early amyloidosis. Chromatin accessibility changes were prominent in excitatory neurons during early pathology, with a later shift to inhibitory neurons, potentially reflecting compensatory mechanisms to mitigate excitatory neuron dysregulation. Despite broadly comparable hippocampal cell composition, transcriptomic comparisons between wild-type and AppNL-G-F mice revealed major gene expression differences, particularly in pathways related to mitochondrial function and protein biosynthesis, preceding severe amyloid plaque deposition. In later stages, upregulation of immune and neuroinflammatory pathways was observed, aligning with established neuroinflammatory processes in AD. Additionally, we identified extensive DNA methylation differences in both the blood and hippocampus of AppNL-G-F mice during early and late stages of pathology. Many differentially methylated regions in the blood, even at early pathology stages, were associated with cis-regulatory elements in the brain and were located near differentially expressed genes in the hippocampus. These regions were enriched in pathways related to brain function, such as neuron development and synaptic processes, indicating a link between blood methylation patterns and brain function. This suggests the potential utility of blood methylation as a biomarker for early amyloidosis detection. Notably, we identified five candidate biomarker genes, including Rbfox1 and Camta1, with epigenetic dysregulation detectable in both the brain and blood prior to severe amyloid accumulation. Our study, leveraging a unique AD mouse model and a multi-omics approach, highlights epigenetic signatures of AD before the onset of clinical symptoms, providing a foundation for future research into early diagnosis and therapeutic strategies, as well as potential biomarkers.
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Project description:Detecting and understanding Alzheimer's disease (AD) in its early stages is essential for uncovering the initial mechanisms behind its neuropathology and devising effective interventions. In this study, we leveraged the humanized AppNL-G-F mouse which exhibits early-onset amyloid pathology along a predictable timeline, to investigate molecular changes in the hippocampus and blood before the onset of severe neuropathology and independent of aging. Employing a multi-omics approach, we identified alterations in chromatin accessibility, gene expression, and DNA methylation associated with early amyloidosis. Chromatin accessibility changes were prominent in excitatory neurons during early pathology, with a later shift to inhibitory neurons, potentially reflecting compensatory mechanisms to mitigate excitatory neuron dysregulation. Despite broadly comparable hippocampal cell composition, transcriptomic comparisons between wild-type and AppNL-G-F mice revealed major gene expression differences, particularly in pathways related to mitochondrial function and protein biosynthesis, preceding severe amyloid plaque deposition. In later stages, upregulation of immune and neuroinflammatory pathways was observed, aligning with established neuroinflammatory processes in AD. Additionally, we identified extensive DNA methylation differences in both the blood and hippocampus of AppNL-G-F mice during early and late stages of pathology. Many differentially methylated regions in the blood, even at early pathology stages, were associated with cis-regulatory elements in the brain and were located near differentially expressed genes in the hippocampus. These regions were enriched in pathways related to brain function, such as neuron development and synaptic processes, indicating a link between blood methylation patterns and brain function. This suggests the potential utility of blood methylation as a biomarker for early amyloidosis detection. Notably, we identified five candidate biomarker genes, including Rbfox1 and Camta1, with epigenetic dysregulation detectable in both the brain and blood prior to severe amyloid accumulation. Our study, leveraging a unique AD mouse model and a multi-omics approach, highlights epigenetic signatures of AD before the onset of clinical symptoms, providing a foundation for future research into early diagnosis and therapeutic strategies, as well as potential biomarkers.
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