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: 9.69). 11/2005; 171(2):327-35. DOI: 10.1083/jcb.200505078
Source: PubMed

ABSTRACT 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 · 5.20 Impact Factor
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    • "In particular, a putative contribution of these proteolytic fragments has been demonstrated in transgenic mice overexpressing AICD. Increased levels of AICD are responsible for a series of events, including the activation of GSK-3␤ [3], hyperphosphorylation and aggregation of tau protein, microtubule destabilization, and reduction of nuclear ␤-catenin levels, thus causing a loss of cell-cell contact mechanisms that may contribute to neurotoxicity in AD. Subsequent neurodegeneration and working memory deficits were also observed in these transgenic mice [37], as well as abnormal spiking events in their electroencephalograms and susceptibility to kainic acid-induced seizures independent of A␤ [38]. "
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    ABSTRACT: The amyloid-β protein precursor (AβPP) can be processed by either the amyloidogenic or the non-amyloidogenic pathway; both pathways lead to release of the AβPP intracellular C-terminal domain (AICD). AICD involvement in signal transduction within Fe65/Tip60 complex is one of the most discussed mechanisms, and different models have been hypothesized to explain the role of AICD within this complex. The analysis of these models in relation to the degradation processes highlights the discrepancy among AICD localization, function, and degradation, leading to the hypothesis that a signaling mechanism may exist which allows AβPP proteolysis to generate either a transcriptionally active fragment or an inactive one with different involvement of proteasome and IDE (insulin-degrading enzyme). Our work aimed to analyze the functional role of AICD within the Fe65/Tip60 complex considering the AICD degradation processes. Our data suggest a correlation between the role of AICD in gene regulation and its removal operated by proteasome activity. Moreover, treatments with IDE inhibitor underlined the presence of an alternative mechanism involved in AICD removal when the latter is not exerting nuclear activity, thus providing clearer support for the existence of at least two mechanisms as previously suggested.
    Journal of Alzheimer's disease: JAD 03/2012; 30(2):393-405. DOI:10.3233/JAD-2012-111961 · 4.15 Impact Factor
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    • "2003 ; von Rotz et al . 2004 ; Ryan and Pimplikar 2005 APP Cell adhesion and migration , neurite outgrowth , synaptogenesis "
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    ABSTRACT: The amyloid-β precursor protein (βAPP) undergoes several cleavages by enzymatic activities called secretases. Numerous studies aimed at studying the biogenesis and catabolic fate of Aβ peptides, the proteinaceous component of the senile plaques that accumulate in Alzheimer's disease-affected brains. Relatively recently, another secretase-mediated β-APP-derived catabolite called APP IntraCellular Domain (AICD) entered the game. Whether AICD corresponded to a biologically inert by-pass product of βAPP processing or whether it could harbor its own function remained questionable. In this study, we review the mechanisms by which AICD is generated and how its production is regulated. Furthermore, we discuss the degradation mechanism underlying its rapid catabolic fate. Finally, we review putative AICD-related functions and more particularly, the numerous studies indicating that AICD could translocate to the nucleus and control at a transcriptional level, the expression of a series of proteins involved in various functions including the control of cell death and Aβ degradation.
    Journal of Neurochemistry 11/2011; 120 Suppl 1:109-24. DOI:10.1111/j.1471-4159.2011.07475.x · 4.24 Impact Factor
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