Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death

Jean, Ying Y.; Ribé, Elena M.; Pero, Maria Elena; Москаленко, Марина; Iqbal, Zarah; Marks, Lianna J.; Greene, Lloyd A.; Troy, Carol M.

doi:10.1042/bj20130556

Cited by 25 publications

(25 citation statements)

References 59 publications

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“…In accord with in vitro studies, we and others have shown that Aβ 1-42 directly infused into the hippocampus elicits neuron death 1,4,9,10 , depicting one of the key features of AD. The degeneration is clearly evident in the vicinity of the injection site as shown by a decreased in the volume of the dentate gyrus that is complemented by increases in markers for degeneration 1 .…”

Section: Discussionmentioning

confidence: 84%

“…These low molecular weight Aβ 1-42 species, but not the fibrils and plaques, have been shown in numerous settings to be most toxic to neurons 1,4,9,[17][18][19] . To determine whether or not oligomeric Aβ 1-42 induces neuron death in the mouse brain Aβ 1-42 (4 µl of 100 µM stock solution) was infused into the DG of the hippocampus in one hemisphere of 9 month old wild-type C57BL/6J mice.…”

Section: Representative Resultsmentioning

confidence: 99%

“…However, mice of any age could be used for the injection. In the past we have experimented on mice that were 16 months old and others have used mice that were 2 months old 9,10 . Only male mice should be used in studies as female mice exhibit estrogen level fluctuations and estrogen is known to have neuroprotective effects 20 .…”

Section: Discussionmentioning

confidence: 99%

“…The direct infusion of oligomeric Aβ into the wild-type mouse brain provides an excellent in vivo model which replicates the neuronal death aspect of amyloidopathy 1,9,10 . Unlike the commonly utilized transgenic mouse models the oligomeric Aβ 1-42 infusion model is ideal for acutely elevating Aβ 1-42 levels in a spatial and temporal manner.…”

Section: Introductionmentioning

confidence: 99%

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Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

Jean

Baleriola

Fà

et al. 2015

JoVE

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Alzheimer's disease is a neurodegenerative disease affecting the aging population. A key neuropathological feature of the disease is the over-production of amyloid-beta and the deposition of amyloid-beta plaques in brain regions of the afflicted individuals. Throughout the years scientists have generated numerous Alzheimer's disease mouse models that attempt to replicate the amyloid-beta pathology. Unfortunately, the mouse models only selectively mimic the disease features. Neuronal death, a prominent effect in the brains of Alzheimer's disease patients, is noticeably lacking in these mice. Hence, we and others have employed a method of directly infusing soluble oligomeric species of amyloid-beta -forms of amyloid-beta that have been proven to be most toxic to neurons -stereotaxically into the brain. In this report we utilize male C57BL/6J mice to document this surgical technique of increasing amyloid-beta levels in a select brain region. The infusion target is the dentate gyrus of the hippocampus because this brain structure, along with the basal forebrain that is connected by the cholinergic circuit, represents one of the areas of degeneration in the disease. The results of elevating amyloid-beta in the dentate gyrus via stereotaxic infusion reveal increases in neuron loss in the dentate gyrus within 1 week, while there is a concomitant increase in cell death and cholinergic neuron loss in the vertical limb of the diagonal band of Broca of the basal forebrain. These effects are observed up to 2 weeks. Our data suggests that the current amyloid-beta infusion model provides an alternative mouse model to address region specific neuron death in a short-term basis. The advantage of this model is that amyloid-beta can be elevated in a spatial and temporal manner. Video LinkThe video component of this article can be found at

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Section: Discussionmentioning

confidence: 84%

Section: Representative Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

Jean

Baleriola

Fà

et al. 2015

JoVE

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“…Previously, we and many others have demonstrated that rodent neurons exposed to amyloid peptides are susceptible of Aβ-induced toxicity and other phenotypes, including tau phosphorylation and synaptic alterations (8)(9)(10)(11)(12).…”

Section: Subhead 4: Empirical Evidence For Jak-stat Dysregulation In mentioning

confidence: 99%

Genetic and real-world clinical data, combined with empirical validation, nominate JAK-STAT signalling as a target for Alzheimer’s Disease therapeutic development

Nevado‐Holgado

Ribé

Thei

et al. 2017

Preprint

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As Genome Wide Association Studies (GWAS) have grown in size, the number of genetic variants that have been nominated for an increasing number of diseases has correspondingly increased. Despite this increase in the number of associated SNPs per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with an orthogonal source of evidence, namely real-world, routinely collected clinical data from more than 6 million patients in order to drive target nomination. First we show that when examined at a pathway level, analysis of all GWAS studies groups Alzheimer’s disease (AD) in a cluster with disorders of immunity and inflammation. Using clinical data we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the JAK-STAT pathway. Using four independent open-science datasets we then find evidence for altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of key drivers of this pathway, providing experimental evidence validating these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence potential target for therapeutic development, and moreover demonstrate a de-novo multi-modal approach to derive information from rapidly increasing genomic datasets.One Sentence SummaryCombining evidence from genome wide association studies, real-world clinical and cohort molecular data together with experimental studies in rodent model systems nominates JAK-STAT signaling as an aetiopathological event in Alzheimer’s disease

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An Animal Model of Alzheimer Disease Based on the Intrahippocampal Injection of Amyloid β-Peptide (1–42)

Facchinetti

Bronzuoli

Scuderi

2017

Methods in Molecular Biology

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The intrahippocampal injection of amyloid beta peptide (1-42) (Aβ) represents one of the most useful animal models of Alzheimer disease. Since none of these available models fully represents the main pathological hallmarks of Alzheimer disease, stereotaxic Aβ infusion provides researchers with an in vivo alternative paradigm. When performed by well-trained individuals, this model is the best-suited one for short-term studies focusing on the effects of Aβ on a specific brain region or circuitry. Here, we describe all methodological phases of such a model.

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Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death

Cited by 25 publications

References 59 publications

Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

Genetic and real-world clinical data, combined with empirical validation, nominate JAK-STAT signalling as a target for Alzheimer’s Disease therapeutic development

An Animal Model of Alzheimer Disease Based on the Intrahippocampal Injection of Amyloid β-Peptide (1–42)

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