Gene Expression profiling of TgCRND8 brains at 18 months
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE318217 | GEO | 2026/02/04
REPOSITORIES: GEO
Similar Datasets
Project description:Sterile neuroinflammation initiated by damage-associated molecular patterns (DAMPs) has been regarded as an important driver in Alzheimer's disease (AD) and can occur prior or independently of the deposition of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFTs). Genetic ablation or pharmacological inhibition of GPR34 reduced microglia activation, Aβ deposition and cognition impairment. Moreover, GPR34 inhibition prevented aging associated neuroinflammation and cognition impairment without the presence of Aβ plaques.
2025-02-05 | GSE216209 | GEO
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:Proctor2013 - Effect of Aβ immunisation
in Alzheimer's disease (stochastic version)
Extension of a previously published
stochastic model (designed to examine some of the key pathways
involved in the aggregation of amyloid-beta (A
β) and
the micro-tubular binding protein tau (
BIOMD0000000286,
BIOMD0000000462))
to include the main processes involved in passive and active
immunisation against A
β
and then to demonstrate the effects of this intervention on soluble
A
β. This
is the stochastic version of the model, the deterministic version
is
BIOMD0000000488.
This model is described in the article:
Investigating interventions
in Alzheimer's disease with computer simulation models.
Proctor CJ, Boche D, Gray DA, Nicoll
JA.
PLoS ONE 2013; 8(9): e73631
Abstract:
Progress in the development of therapeutic interventions to
treat or slow the progression of Alzheimer's disease has been
hampered by lack of efficacy and unforeseen side effects in
human clinical trials. This setback highlights the need for new
approaches for pre-clinical testing of possible interventions.
Systems modelling is becoming increasingly recognised as a
valuable tool for investigating molecular and cellular
mechanisms involved in ageing and age-related diseases.
However, there is still a lack of awareness of modelling
approaches in many areas of biomedical research. We previously
developed a stochastic computer model to examine some of the
key pathways involved in the aggregation of amyloid-beta (Aβ)
and the micro-tubular binding protein tau. Here we show how we
extended this model to include the main processes involved in
passive and active immunisation against Aβ and then demonstrate
the effects of this intervention on soluble Aβ, plaques,
phosphorylated tau and tangles. The model predicts that
immunisation leads to clearance of plaques but only results in
small reductions in levels of soluble Aβ, phosphorylated tau
and tangles. The behaviour of this model is supported by
neuropathological observations in Alzheimer patients immunised
against Aβ. Since, soluble Aβ, phosphorylated tau and tangles
more closely correlate with cognitive decline than plaques, our
model suggests that immunotherapy against Aβ may not be
effective unless it is performed very early in the disease
process or combined with other therapies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000634.
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.
2024-09-02 | BIOMD0000000634 | BioModels
Project description:Proctor2013 - Effect of Aβ immunisation
in Alzheimer's disease (deterministic version)
Extension of a previously published stochastic model (designed
to examine some of the key pathways involved in the aggregation
of amyloid-beta (Aβ) and the micro-tubular binding protein
tau (
BIOMD0000000286,
BIOMD0000000462))
to include the main processes involved in passive and active
immunisation against Aβ and then to demonstrate the effects
of this intervention on soluble Aβ. This is the
deterministic version of the model, the stochastic version is
BIOMD0000000634.
This model is described in the article:
Investigating interventions
in Alzheimer's disease with computer simulation models.
Proctor CJ, Boche D, Gray DA, Nicoll
JA.
PLoS ONE 2013; 8(9): e73631
Abstract:
Progress in the development of therapeutic interventions to
treat or slow the progression of Alzheimer's disease has been
hampered by lack of efficacy and unforeseen side effects in
human clinical trials. This setback highlights the need for new
approaches for pre-clinical testing of possible interventions.
Systems modelling is becoming increasingly recognised as a
valuable tool for investigating molecular and cellular
mechanisms involved in ageing and age-related diseases.
However, there is still a lack of awareness of modelling
approaches in many areas of biomedical research. We previously
developed a stochastic computer model to examine some of the
key pathways involved in the aggregation of amyloid-beta (Aβ)
and the micro-tubular binding protein tau. Here we show how we
extended this model to include the main processes involved in
passive and active immunisation against Aβ and then demonstrate
the effects of this intervention on soluble Aβ, plaques,
phosphorylated tau and tangles. The model predicts that
immunisation leads to clearance of plaques but only results in
small reductions in levels of soluble Aβ, phosphorylated tau
and tangles. The behaviour of this model is supported by
neuropathological observations in Alzheimer patients immunised
against Aβ. Since, soluble Aβ, phosphorylated tau and tangles
more closely correlate with cognitive decline than plaques, our
model suggests that immunotherapy against Aβ may not be
effective unless it is performed very early in the disease
process or combined with other therapies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000488.
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.
2024-09-02 | BIOMD0000000488 | BioModels
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: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:Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia (DAM) states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of Alzheimer's disease. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.
2021-06-03 | GSE176032 | GEO
Project description:Amyloid plaque heterogeneity is a hallmark of Alzheimer's disease (AD), yet the mechanisms governing plaque diversity and its relationship to disease progression remain poorly understood. Although both diffuse and neuritic plaques are present in AD brain tissue, we do not know how these distinct conformations arise or influence pathological outcomes. Here, we developed transgenic mouse models expressing identical APP constructs in either glutamatergic or GABAergic neurons to investigate how cellular context shapes amyloid pathology. This approach revealed that the cellular source of APP influences both the biochemical composition and structural characteristics of resulting Aβ deposits. APP expressed in GABAergic neurons generated exclusively diffuse plaques with elevated Aβ42/Aβ40 ratios that failed to induce gliosis, while glutamatergic expression produced primarily neuritic plaques surrounded by activated microglia. Differences in deposit characteristics appeared to arise from fundamental variations in APP processing between excitatory and inhibitory neurons. Moreover, only neuritic plaques generated by glutamatergic neurons caused behavioral deficits, while diffuse plaques from GABAergic neurons did not impair cognition despite substantial amyloid burden. These findings may provide new insight into the mechanisms underlying amyloid heterogeneity in AD and suggest that plaque conformation, rather than simply amyloid load, may influence cognitive trajectories. snRNA-seq revealed that microglia from the excitatory models showed many DAM genes were upregulated, which were absent in the inhibitory model. The data also revealed there were no changes in expression of key APP processing enzymes between excitatory or inhibitory neurons in each model.
2026-01-07 | GSE292822 | GEO
Project description:The two hallmarks of Alzheimer’s disease (AD) are A-amyloid- (A) plaques and neurofibrillary tangles marked by phosphorylated tau. There is compelling evidence that aggregating A drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely there is a growing realization that non-fibrillar (oligomeric) forms of Aβ mediate toxicity in AD. Using quantitative proteomics, we find that AD brain sarkosyl-insoluble pellets are greatly enriched with A at almost equimolar levels to N-terminal truncated microtubule binding region (MTBR) isoforms of tau with multiple post-translational modifications (PTMs). The extracted R3-R4 tau peptides are 100-fold higher compared to N-terminus intact tau peptides. Substantial proportions of site-specific phosphorylation at T181 (~ 22 %) and T217 (~ 16 %) along with other PTMs in the proline rich region (PRR) and MTBR indicate a regional susceptibility of PTMs in aggregated tau. Immuno-electron microscopy reveals that co-purified A and tau co-localize to globular non-filamentous aggregates.
2022-06-04 | PXD032389 | Pride
Project description:The two hallmarks of Alzheimer’s disease (AD) are A-amyloid- (A) plaques and neurofibrillary tangles marked by phosphorylated tau. There is compelling evidence that aggregating A drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely there is a growing realization that non-fibrillar (oligomeric) forms of Aβ mediate toxicity in AD. Using quantitative proteomics, we find that AD brain sarkosyl-insoluble pellets are greatly enriched with A at almost equimolar levels to N-terminal truncated microtubule binding region (MTBR) isoforms of tau with multiple post-translational modifications (PTMs). The extracted R3-R4 tau peptides are 100-fold higher compared to N-terminus intact tau peptides. Substantial proportions of site-specific phosphorylation at T181 (~ 22 %) and T217 (~ 16 %) along with other PTMs in the proline rich region (PRR) and MTBR indicate a regional susceptibility of PTMs in aggregated tau. Immuno-electron microscopy reveals that co-purified A and tau co-localize to globular non-filamentous aggregates.
2022-06-04 | PXD032372 | Pride