Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA270888 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we particularly focused on short ncRNA expression profiling of three, ten and twenty month old triple transgenic mouse model for Alzheimers disease (Oddo et al.; 2003;Neuron). These mice harbor presenilin PS1(M146V), APP(Swedish) and tau(P301L) mutations and develop beta-amyloid plaques and at later stages also a tau pathology. Controls are age matched B6129SF2/J mice.
2014-10-31 | E-MTAB-2738 | biostudies-arrayexpress
Project description:Loss-of-function mutations in TREM2 (triggering receptor expressed on myeloid cells 2) strongly increase Alzheimer’s disease (AD) risk. Preclinical models using Trem2 deletion or overexpression have revealed a protective Trem2 function related to β-amyloid accumulation, a process that is most prominent during the pre-diagnosis stages of AD. The role of TREM2 in later AD stages characterized by tau-mediated neurodegeneration is less clear. To understand Trem2 function in the context of both β-amyloid and tau pathologies, we examined Trem2-deficient mice expressing mutant tau alone (pR5-183 model) or in the TauPS2APP model, in which β-amyloid pathology exacerbates tau pathology and neurodegeneration. Single-cell RNA-sequencing in these models revealed robust disease-associated microglia (DAM) activation in TauPS2APP mice that was both amyloid-dependent and Trem2-dependent. In the presence of β-amyloid pathology, Trem2 deletion further exacerbated tau accumulation and spreading and promoted brain atrophy. Without β-amyloid pathology, Trem2 deletion did not affect these processes. Therefore, TREM2 may slow AD progression and reduce tau-driven neurodegeneration by restricting the degree to which β-amyloid facilitates the spreading of pathogenic tau
2021-02-24 | GSE153895 | GEO
Project description:Transgenic mouse models have been widely used to investigate the pathology of Alzheimer’s disease (AD). To elucidate underlying mechanisms of AD pathogenesis by amyloid beta (Aβ) and tau, we have generated a novel animal model of AD; ADLP - APT mice (Alzheimer’s Disease-Like Pathology) – carrying mutations of human amyloid precursor protein (APP), human presenilin-1 (PS1) and human tau. We profiled 9,824 proteins in the hippocampus of ADLP model mice using quantitative proteomics. To identify functional signatures in pathology of ADLP - APT mice, in-depth bioinformatics analysis was performed. For a longitudinal change of differentially expressed proteins (DEPs), we identified ADLP - APT mice hippocampal proteome in an age-dependent manner. Network maps of interactome between Aβ and tau in newly generated ADLP - APT mice reveal relationship between accelerated NFT pathology of AD and proteomic changes.
2018-01-25 | PXD006214 | Pride
Project description:The purpose of this project was to compare whole genome expression in 5 transgenic mice with human genes for dementia that result in either plaques or tangle pathology to the expression in wild-type control mice and to each other at different stages of disease progression. Total RNA was obtained from hippocampus, cortex and cerebellum in four lines of ‘amyloid’ transgenic mice (mutant human APP and APP/PSEN1 genes) and ‘TAU’ transgenic mice (mutant human MAPT gene) as well as wild-type control mice at 8,16, 32 and 72 weeks
2014-12-24 | E-GEOD-64398 | biostudies-arrayexpress
Project description:The abnormal regulation of amyloid-b (Ab) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimerâs disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Ab deposition and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Ab metabolism, including Tau, Mapk, and Sirt1. We used RNA-Seq to analyse the hippocampus of 3xTg-AD mice lacking the miR-132/212 cluster as well as Neuro2a cells overexpressing miR-132 mimics.
2016-07-17 | E-GEOD-84481 | biostudies-arrayexpress
Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
2021-02-20 | GSE148822 | GEO
Project description:Non-neuronal responses in neurodegenerative disease have received increasing attention as important contributors to disease pathogenesis and progression. Here we utilize single-cell RNA-sequencing to broadly characterize responses of twelve cell types in three different mouse models of Alzheimer’s Disease, capturing the effects of tau-only, amyloid-only, or combined tau- amyloid pathology. We characterize microglia, oligodendrocyte, astrocyte, and T cell responses and compare them across these models. Notably, we identify two distinct transcriptional states for oligodendrocytes induced during disease and determine their spatial distribution. Furthermore, we explore the impact of Trem2 deletion in the context of combined pathology. Trem2 knockout mice exhibit severely blunted microglial responses to combined tau and amyloid pathology, but responses from non-microglial cell types (oligodendrocytes, astrocytes, and T cells) are relatively unchanged. These results delineate core transcriptional states that are accessible in the degenerating brain and how they are influenced by a key Alzheimer’s Disease risk gene, Trem2.
2021-11-12 | GSE160512 | GEO
Project description:There is accumulating evidence that amyloid beta and tau proteins may act synergistically to cause synapse and neural circuit degeneration in Alzheimer’s disease. In order to study this, we designed a new mouse model which lacks endogenous mouse tau, but expresses both the APP/PS1 transgene, which causes well-characterised plaque-associated synapse loss, and also reversibly expresses wild-type human tau (which can be suppressed with doxycycline). We examined the transcriptional changes in the frontal cortex of this mouse model, along with behaviour, pathology, synaptic plasticity, synapse degeneration and accumulation of amyloid beta and tau at synapses, and compared with littermate control genotypes: those lacking endogenous mouse tau, those lacking endogenous mouse tau but expressing the APP/PS1 transgene only, and those lacking endogenous mouse tau but reversibly expressing wild-type human tau only.
2019-11-12 | E-MTAB-7856 | biostudies-arrayexpress
Project description:The abnormal regulation of amyloid-b (Ab) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer’s disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Ab deposition and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Ab metabolism, including Tau, Mapk, and Sirt1.
2016-07-17 | GSE84481 | GEO
Project description:Extracellular amyloid-β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response in the presence of Aβ or tau pathology. We systematically compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T-cells blocked tau-mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN-γ and PD-1signaling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.
2023-03-01 | GSE221856 | GEO