Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain

Department of Pathology and Cell Biology Program, Case Western Reserve University, Cleveland, OH 44106, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 11/2005; 171(2):327-35. DOI: 10.1083/jcb.200505078
Source: PubMed


Amyloid precursor protein (APP), implicated in Alzheimer's disease, is a trans-membrane protein of undetermined function. APP is cleaved by gamma-secretase that releases the APP intracellular domain (AICD) in the cytoplasm. In vitro studies have implicated AICD in cell signaling and transcriptional regulation, but its biologic relevance has been uncertain and its in vivo function has not been examined. To investigate its functional role, we generated AICD transgenic mice, and found that AICD causes significant biologic changes in vivo. AICD transgenic mice show activation of glycogen synthase kinase-3beta (GSK-3beta) and phosphorylation of CRMP2 protein, a GSK-3beta substrate that plays a crucial role in Semaphorin3a-mediated axonal guidance. Our data suggest that AICD is biologically relevant, causes significant alterations in cell signaling, and may play a role in axonal elongation or pathfinding.

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    • "Here we provide evidence that the APP/AICD system contributes to regulate the GSK3β activity in trisomic aNPCs. This is in agreement with a study that demonstrated the activation of GSK3β and phosphorylation of CRMP2 in transgenic mice expressing AICD (Ryan and Pimplikar, 2005). Since the levels of mRNA transcripts and total protein levels of GSK3β were not changed in trisomic mice, the AICD-dependent modulation of GSK3β activation must be mediated by a non-transcriptional mechanism. "
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    ABSTRACT: Intellectual disability in Down syndrome (DS) appears to be related to severe neurogenesis impairment during brain development. The molecular mechanisms underlying this defect are still largely unknown. Accumulating evidence has highlighted the importance of GSK3β signaling for neuronal precursor proliferation/differentiation. In neural precursor cells (NPCs) from Ts65Dn mice and human fetuses with DS, we found reduced GSK3β phosphorylation and, hence, increased GSK3β activity. In cultures of trisomic subventricular-zone-derived adult NPCs (aNPCs) we found that deregulation of GSK3β activity was due to higher levels of the AICD fragment of the trisomic gene APP that directly bound to GSK3β. We restored GSK3β phosphorylation in trisomic aNPCs using either lithium, a well-known GSK3β inhibitor, or using a 5-HT receptor agonist or fluoxetine, which activated the serotonin receptor 5-HT1A. Importantly, this effect was accompanied by restoration of proliferation, cell fate specification and neuronal maturation. In agreement with results obtained in vitro, we found that early treatment with fluoxetine, which was previously shown to rescue neurogenesis and behavior in Ts65Dn mice, restored GSK3β phosphorylation. These results provide a link between GSK3β activity alteration, APP triplication and the defective neuronal production that characterizes the DS brain. Knowledge of the molecular mechanisms underlying neurogenesis alterations in DS may help to devise therapeutic strategies, potentially usable in humans. Results suggest that drugs that increase GSK3β phosphorylation, such as lithium or fluoxetine, may represent useful tools for the improvement of neurogenesis in DS.
    Neurobiology of Disease 07/2014; 67. DOI:10.1016/j.nbd.2014.03.003 · 5.08 Impact Factor
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    • "In addition, PS1 regulates kinesin-related axonal transport by a mechanism involving GSK-3β activity (Ryan and Pimplikar, 2005) and the modulation of its role in controlling kinesin binding to microtubules at sites of vesicle release (Pigino et al., 2003). "
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    ABSTRACT: Alzheimer disease (AD) is the most common form of age-related dementia. The etiology of AD is considered to be multifactorial as only a negligible percentage of cases have a familial or genetic origin. Glycogen synthase kinase-3 (GSK-3) is regarded as a critical molecular link between the two histopathological hallmarks of the disease, namely senile plaques and neurofibrillary tangles. In this review, we summarize current data regarding the involvement of this kinase in several aspects of AD development and progression, as well as key observations highlighting GSK-3 as one of the most relevant targets for AD treatment.
    Frontiers in Molecular Neuroscience 05/2014; 7:46. DOI:10.3389/fnmol.2014.00046 · 4.08 Impact Factor
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    • "This multiprotein complex is involved in transcriptional activation151617, though the specific role(s) of the AICD in such process, its full set of partner proteins as well as the range of genes it can target are still debated318. The best established AICD target gene codes for the pro-apoptotic tetraspannin KAI1, also known as CD8214151920. "
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    ABSTRACT: Amyloid precursor protein (APP) intracellular domain (AICD) is a product of APP processing with transcriptional modulation activity, whose overexpression causes various Alzheimer's disease (AD)-related dysfunctions. Here we report that 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid) (CHF5074), a compound that favorably affects neurodegeneration, neuroinflammation and memory deficit in transgenic mouse models of AD, interacts with the AICD and impairs its nuclear activity. In neuroglioma-APPswe cells, CHF5074 shifted APP cleavage from Aβ42 to the less toxic Aβ38 peptide without affecting APP-C-terminal fragment, nor APP levels. As revealed by photoaffinity labeling, CHF5074 does not interact with γ-secretase, but binds to the AICD and lowers its nuclear translocation. In vivo treatment with CHF5074 reduced AICD occupancy as well as histone H3 acetylation levels and transcriptional output of the AICD-target gene KAI1. The data provide new mechanistic insights on this compound, which is under clinical investigation for AD treatment/prevention, as well as on the contribution of the AICD to AD pathology.
    Scientific Reports 04/2014; 4:4618. DOI:10.1038/srep04618 · 5.58 Impact Factor
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