Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-nuclei transcriptome sequencing of 5xFAD mouse brain hemisphere with myelin dysfunction

ABSTRACT: The aim of the dataset is to identify cell heterogeneity changes under myelin abnormalities. Alzheimer’s disease (AD) is the most common form of dementia and neurodegenerative disease with increasing prevalence due to longer lifespan in the human population. Why aging constitutes the greatest risk factor for development of AD, however, remains poorly understood. Aging markedly affects oligodendrocytes and the structural integrity of their myelin sheaths which also causes secondary tissue inflammation. We propose a mechanistic link between aging-associated myelin dysfunction and the deposition of Amyloid-ß (Aß) as primary neuropathological hallmark of early AD and hypothesized that breakdown of myelin - especially in cortical regions – is an upstream driver of amyloid deposition in AD. Here, we show that in transgenic mouse models of AD, genetically induced myelin defects by Cnp or Plp1 depletion, as well as direct demyelination are potent drivers of amyloid deposition in vivo as shown by light sheet microscopy imaging. At transcriptomic level, bulk and single-cell RNA sequencing revealed successfully induced disease-associated-microglia (DAM)-like phenotypes in Cnp-/- animals. These activated microglia, however, are primarily engaged with myelin seemingly preventing the protective reactions of the microglia pool to Aß plaques. Our work, therefore, identifies myelin aging as a previously overlooked risk factor for AD and makes the case for myelin health-directed therapies in AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE208683 | GEO | 2023/03/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcriptome profiling of mouse brain microglia in Cnp null mice with 5xFAD background

Project description:Alzheimer’s disease (AD) is the most common form of dementia and neurodegenerative disease with increasing prevalence due to longer lifespan in the human population. Why aging constitutes the greatest risk factor for development of AD, however, remains poorly understood. Aging markedly affects oligodendrocytes and the structural integrity of their myelin sheaths which also causes secondary tissue inflammation. We propose a mechanistic link between aging-associated myelin dysfunction and the deposition of Amyloid-ß (Aß) as primary neuropathological hallmark of early AD and hypothesized that breakdown of myelin - especially in cortical regions – is an upstream driver of amyloid deposition in AD. Here, we show that in transgenic mouse models of AD, genetically induced myelin defects by Cnp or Plp1 depletion, as well as direct demyelination are potent drivers of amyloid deposition in vivo as shown by light sheet microscopy imaging. At transcriptomic level, bulk and single-cell RNA sequencing revealed successfully induced disease-associated-microglia (DAM)-like phenotypes in Cnp-/- animals. These activated microglia, however, are primarily engaged with myelin seemingly preventing the protective reactions of the microglia pool to Aß plaques. Our work, therefore, identifies myelin aging as a previously overlooked risk factor for AD and makes the case for myelin health-directed therapies in AD.

2023-03-20 | GSE178296 | GEO

Single-nuclei transcriptome sequencing of mouse grey and white matter under myelin abnormalities

Project description:The aim of the dataset is to identify cell heterogeneity changes under myelin abnormalities. Alzheimer’s disease (AD) is the most common form of dementia and neurodegenerative disease with increasing prevalence due to longer lifespan in the human population. Why aging constitutes the greatest risk factor for development of AD, however, remains poorly understood. Aging markedly affects oligodendrocytes and the structural integrity of their myelin sheaths which also causes secondary tissue inflammation. We propose a mechanistic link between aging-associated myelin dysfunction and the deposition of Amyloid-ß (Aß) as primary neuropathological hallmark of early AD and hypothesized that breakdown of myelin - especially in cortical regions – is an upstream driver of amyloid deposition in AD. Here, we show that in transgenic mouse models of AD, genetically induced myelin defects by Cnp or Plp1 depletion, as well as direct demyelination are potent drivers of amyloid deposition in vivo as shown by light sheet microscopy imaging. At transcriptomic level, bulk and single-cell RNA sequencing revealed successfully induced disease-associated-microglia (DAM)-like phenotypes in Cnp-/- animals. These activated microglia, however, are primarily engaged with myelin seemingly preventing the protective reactions of the microglia pool to Aß plaques. Our work, therefore, identifies myelin aging as a previously overlooked risk factor for AD and makes the case for myelin health-directed therapies in AD.

2023-03-20 | GSE178295 | GEO

Expression data from THP-1 cells treated with GSK3ß inhibitors

Project description:The accumulation of amyloid-ß (Aß) peptides in the brain is a crucial step in the pathogenesis of Alzheimer`s disease (AD). Several studies indicate that microglia cells in the brain have the ability to internalize Aß by phagocytosis and might therefore play a protective role in AD. However, the mechanisms underlying Aß clearance remain unresolved. We have found that small molecule inhibitors of the ubiquitous glycogen synthase kinase 3ß (GSK3ß) stimulate the uptake of Aß by human THP-1 monocytes and primary murine microglia cells. To investigate how GSK3ß inhibitors might stimulate Aß uptake, we conducted microarray-based gene expression analyses of THP-1 cells after treatment with three different GSK3ß inhibitors. We identified a subset of genes similarly altered by all three inhibitors, including chemokines and surface receptors that have been linked to the regulation of microglial activation and phagocytosis.

2020-11-30 | GSE85238 | GEO

The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques (KW)

Project description:Microglia are involved in Alzheimer’s disease (AD) by adopting activated phenotypes. How ageing in the absence or presence of β-amyloid (Aβ) deposition in different brain areas affects this response and whether sex and AD risk genes are involved, remains however largely unknown. Here we analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from cortex and hippocampus of male and female AppNL-G-F at 4 different stages of Aβ deposition and in age-matched control mice. We demonstrate that microglia adopt two major activated states during normal aging and after exposure to amyloid plaques. One of the responses (activated response microglia, ARM) is enhanced in particular by amyloid plaques and is strongly enriched with AD risk genes. The ARM response is not homogeneous, as subgroups of microglia overexpressing MHC type II and tissue repair genes (Dkk2, Gpnmb, Spp1) are induced upon prolonged Aβ exposure. Microglia in female mice advance faster in the activation trajectories. Similar activated states were also found in a second AD model and in human brain. We demonstrate that abolishing the expression of Apoe, the major genetic risk factor for AD, impairs the establishment of ARMs, while the second microglia response type, enriched for interferon response genes, remains unaffected. Our data indicate that ARMs are the converging point of multiple AD risk factors.

2019-04-23 | GSE127892 | GEO

The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques (CDEP)

2019-04-23 | GSE127884 | GEO

The genetic landscape for amyloid beta nucleation accurately discriminates familial Alzheimer’s disease mutations

Project description:Alzheimer’s Disease (AD) is the most common form of dementia and a leading global cause of human mortality and morbidity. Amyloid plaques of the amyloid beta (Aß) peptide are a universal pathological hallmark of AD and rare mutations in Aß can cause familial forms of AD (fAD). However, hundreds of additional mutations in Aß of uncertain significance are likely to exist in the human population, making clinical interpretation of genetic variation a difficult challenge even in this short peptide. Here, we use deep mutagenesis to quantify the effects of all possible single nucleotide variants and thousands of double mutations on the ability of Aß to nucleate amyloid fibrils in vivo. This data provides the first comprehensive view of how mutations alter the nucleation of an amyloid, reveals a modular organisation of mutational effects in Aß, and demonstrates the importance of charge in preventing nucleation. Moreover, the in vivo nucleation data, unlike computational predictors, accurately discriminates the known dominant fAD mutations. These results illustrate how deep mutagenesis can be used to genetically validate assays as discovery platforms. They also further prioritize nucleation as the critical biochemical event to target in order to prevent and treat AD.

2021-02-02 | GSE151147 | GEO

Expression profiling of laser-microdissected tissue from Tg2576 plaque-depositing mouse model of Alzheimer's disease

Project description:Amyloid-ß (Aß) plaques are pathological hallmarks of Alzheimer disease. However, the precise neuropathological changes that occur in brain in response to amyloid deposition are largely unknown. To study the molecular mechanism(s) responsible for Aß-mediated neuropathology, we performed a gene expression analysis on laser-microdissected brain tissue of Tg2576 mice compared to their littermate controls.

2014-11-04 | GSE15056 | GEO

Expression profiling of laser-microdissected tissue from APPPS1 plaque-depositing mouse model of Alzheimer's disease

Project description:Amyloid-ß (Aß) plaques are pathological hallmarks of Alzheimer disease. However, the precise neuropathological changes that occur in brain in response to amyloid deposition are largely unknown. To study the molecular mechanism(s) responsible for Aß-mediated neuropathology, we performed a gene expression analysis on frontal neocortical brain tissue of APPPS1 mice compared to their littermate controls.

2014-11-04 | GSE15058 | GEO

Puri2010 - Mathematical Modeling for the Pathogenesis of Alzheimer's Disease

Project description:Puri2010 - Mathematical Modeling for the Pathogenesis of Alzheimer's Disease Puri2010 - Mathematical Modeling for the Pathogenesis of Alzheimer's Disease Encoded non-curated model. Issues: - Confusing replacement of α16 when t = 3 years - Confusing 4th rate equation This model is described in the article: Mathematical modeling for the pathogenesis of Alzheimer's disease. Puri IK, Li L. PLoS ONE 2010; 5(12): e15176 Abstract: Despite extensive research, the pathogenesis of neurodegenerative Alzheimer's disease (AD) still eludes our comprehension. This is largely due to complex and dynamic cross-talks that occur among multiple cell types throughout the aging process. We present a mathematical model that helps define critical components of AD pathogenesis based on differential rate equations that represent the known cross-talks involving microglia, astroglia, neurons, and amyloid-? (A?). We demonstrate that the inflammatory activation of microglia serves as a key node for progressive neurodegeneration. Our analysis reveals that targeting microglia may hold potential promise in the prevention and treatment of AD. This model is hosted on BioModels Database and identified by: MODEL1409240001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

2015-04-15 | MODEL1409240001 | BioModels

An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation

Project description:Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type - amino acid (AA) substitutions - despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate the first comprehensive atlas of diverse variant effects for a disease protein, amyloid beta (Aß) that aggregates in Alzheimer’s disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD variants and many mutations beyond substitutions that accelerate Aß aggregation. Truncations, substitutions, insertions, single- and multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are strongly enriched in the polar N-terminus of Aß. This first comparative atlas for any disease gene highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.

2022-10-27 | GSE193837 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data