Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE21137 | GEO | 2010/04/20
SECONDARY ACCESSION(S): PRJNA126653
REPOSITORIES: GEO
Similar Datasets
Project description:We compare here the neurodegenerative processes observed in the hippocampus of bitransgenic mice with chronically altered levels of cAMP-response element-binding protein (CREB) function. The combination of genome-wide transcriptional profiling of degenerating hippocampal tissue with microscopy analyses reveals that the sustained inhibition of CREB function in A-CREB mice is associated with dark neuron degeneration, whereas its strong chronic activation in VP16-CREB mice primarily causes excitotoxic cell death and inflammation. Furthermore, the meta-analysis with gene expression profiles available in public databases identifies relevant common markers to other neurodegenerative processes and highlights the importance of the immune response in neurodegeneration. Overall, these analyses define the ultrastructural and transcriptional signatures associated with these two forms of hippocampal neurodegeneration, confirm the importance of fine-tuned regulation of CREBdependent gene expression for CA1 neuron survival and function, and provide novel insight into the function of CREB in the etiology of neurodegenerative processes. For each mouse genome 430 2.0 gene expression array (Affymetrix, Santa Clara, CA, USA), total RNA was extracted from the hippocampi of three to four mice with the same age, sex, and genotype to produce one pooled sample. We analyzed three late A-CREB pooled samples (6-week-old mice) and three late VP16-CREB pooled samples (3-week-off dox) with their corresponding control littermate samples (three pooled samples for each strain). To compare with early changes, we included two pooled A-CREB early samples (3-week-old mice) and two pooled VP16-CREB early samples (1-week-off dox) with their corresponding control littermate samples. In the case of A-CREB mice, we used the dataset GSE14320. We prepared new samples from bitransgenic mice and control littermates 1 week after transgene induction and hybridized them to mouse genome 430 2.0 genechips. The arrays were hybridized, washed, and screened for quality according to the manufacturerâs protocol.
2010-04-28 | E-GEOD-21137 | biostudies-arrayexpress
Project description:The cAMP responsive element binding protein (CREB) pathway has been involved in two major cascades of gene expression regulating neuronal function. The first one presents CREB as a critical component of the molecular switch that control longlasting forms of neuronal plasticity and learning. The second one relates CREB to neuronal survival and protection. To investigate the role of CREB-dependent gene expression in neuronal plasticity and survival in vivo, we generated bitransgenic mice expressing A-CREB, an artificial peptide with strong and broad inhibitory effect on the CREB family, in forebrain neurons in a regulatable manner. The expression of ACREB in hippocampal neurons impaired L-LTP, reduced intrinsic excitability and the susceptibility to induced seizures, and altered both basal and activity-driven gene expression. In the long-term, the chronic inhibition of CREB function caused severe loss of neurons in the CA1 subfield as well as in other brain regions. Our experiments confirmed previous findings in CREB deficient mutants and revealed new aspects of CREB-dependent gene expression in the hippocampus supporting a dual role for CREB-dependent gene expression regulating intrinsic and synaptic plasticity and promoting neuronal survival. manufacturer's protocol.
2009-01-12 | GSE14320 | GEO
Project description:The cAMP responsive element binding protein (CREB) pathway has been involved in two major cascades of gene expression regulating neuronal function. The first one presents CREB as a critical component of the molecular switch that control longlasting forms of neuronal plasticity and learning. The second one relates CREB to neuronal survival and protection. To investigate the role of CREB-dependent gene expression in neuronal plasticity and survival in vivo, we generated bitransgenic mice expressing A-CREB, an artificial peptide with strong and broad inhibitory effect on the CREB family, in forebrain neurons in a regulatable manner. The expression of ACREB in hippocampal neurons impaired L-LTP, reduced intrinsic excitability and the susceptibility to induced seizures, and altered both basal and activity-driven gene expression. In the long-term, the chronic inhibition of CREB function caused severe loss of neurons in the CA1 subfield as well as in other brain regions. Our experiments confirmed previous findings in CREB deficient mutants and revealed new aspects of CREB-dependent gene expression in the hippocampus supporting a dual role for CREB-dependent gene expression regulating intrinsic and synaptic plasticity and promoting neuronal survival. manufacturer's protocol. Experiment Overall Design: Each sample contained total RNA from the hippocampi of a group of 3-4 three weeks old mice. We obtained duplicate samples for each experimental condition (in total 14 WT and 20 A-CREB mice where used in this experiment). Mouse Genome 430 2.0 genechips were hybridized, stained, washed and screened for quality according to the manufacturer's protocol.
2009-01-17 | E-GEOD-14320 | biostudies-arrayexpress
Project description:Epidemiological studies suggest that consumption of caffeine, the most commonly consumed psychoactive substances found in coffee, tea or soft drinks reduces the risk of developing Alzheimer’s disease (AD). While previous studies employing transgenic AD mouse models reported on reduced amyloid plaque load or an amelioration of behavioral deficits, there is only limited information on its potential effects on neurodegeneration. In the current study, we assessed whether long-term caffeine consumption affects hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. Treatment over a 4 months period reduced hippocampal neuron loss, rescued learning and memory deficits and ameliorates impaired neurogenesis. Neuron-specific hippocampal transcriptome analysis revealed an altered expression profile with an up-regulation of genes linked to synaptic function and processes, as well as neural progenitor proliferation. Treatment of 5xFAD mice with the same paradigm also rescued behavioral deficits, however, without affecting extracellular amyloid-beta (Abeta) levels or altered APP processing.
2021-12-13 | GSE183323 | GEO
Project description:Clarke2000 - One-hit model of cell death in
neuronal degenerations
This one-hit model fits different
neuronal-death associated diseases for different animal
models.
This model is described in the article:
A one-hit model of cell
death in inherited neuronal degenerations.
Clarke G, Collins RA, Leavitt BR,
Andrews DF, Hayden MR, Lumsden CJ, McInnes RR.
Nature 2000 Jul; 406(6792):
195-199
Abstract:
In genetic disorders associated with premature neuronal
death, symptoms may not appear for years or decades. This delay
in clinical onset is often assumed to reflect the occurrence of
age-dependent cumulative damage. For example, it has been
suggested that oxidative stress disrupts metabolism in
neurological degenerative disorders by the cumulative damage of
essential macromolecules. A prediction of the cumulative damage
hypothesis is that the probability of cell death will increase
over time. Here we show in contrast that the kinetics of
neuronal death in 12 models of photoreceptor degeneration,
hippocampal neurons undergoing excitotoxic cell death, a mouse
model of cerebellar degeneration and Parkinson's and
Huntington's diseases are all exponential and better explained
by mathematical models in which the risk of cell death remains
constant or decreases exponentially with age. These kinetics
argue against the cumulative damage hypothesis; instead, the
time of death of any neuron is random. Our findings are most
simply accommodated by a 'one-hit' biochemical model in which
mutation imposes a mutant steady state on the neuron and a
single event randomly initiates cell death. This model appears
to be common to many forms of neurodegeneration and has
implications for therapeutic strategies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000538.
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 | BIOMD0000000538 | BioModels
Project description:Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain itself and which strategies most potently mitigate these processes, particularly in individuals genetically predisposed to neurodegeneration. We developed a high-intensity ultrasound platform to inflict mechanical injury to iPSC-derived cortical organoids. Mechanically injured organoids elicit several classic hallmarks of TBI including neuron death, tau phosphorylation, and TDP-43 phosphorylation and nuclear egress. We found that deep layer excitatory neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes loss-of-function and cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuron death after brain injury, and we present a scalable, genetically-flexible cerebral organoid model that may enable identification of additional modifiers downstream of mechanical stress.
2024-03-04 | GSE260532 | GEO
Project description:Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain itself and which strategies most potently mitigate these processes, particularly in individuals genetically predisposed to neurodegeneration. We developed a high-intensity ultrasound platform to inflict mechanical injury to iPSC-derived cortical organoids. Mechanically injured organoids elicit several classic hallmarks of TBI including neuron death, tau phosphorylation, and TDP-43 phosphorylation and nuclear egress. We found that deep layer excitatory neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes loss-of-function and cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuron death after brain injury, and we present a scalable, genetically-flexible cerebral organoid model that may enable identification of additional modifiers downstream of mechanical stress.
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2014-02-18 | GSE55069 | GEO
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