Regulation of Secretion of Alzheimer Amyloid Precursor Protein by the Mitogen‐Activated Protein Kinase Cascade

Desdouits-Magnen, Juliette; Desdouits, Frédéric; Takeda, Shuji; Syu, Li-Jyun; Saltiel, Alan R.; Buxbaum, Joseph D.; Czernik, Andrew J.; Nairn, Angus C.; Greengard, Paul

doi:10.1046/j.1471-4159.1998.70020524.x

Cited by 108 publications

(79 citation statements)

References 32 publications

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“…32 However, for the latter mechanism as it relates to APP metabolism, there are contrasting reports. Desdouit-Magnen et al 33 were not able to demonstrate a block of carbacholmediated sAPPa release in PC12-M1 cells treated with the MEK inhibitor PD98059. On the same cellular model, however, Haring et al 13 showed a significant inhibition of carbachol-mediated sAPPa release by PD98059.…”

Section: Discussionmentioning

confidence: 91%

“…Interestingly, no differences in the activation of the MAP-kinase system were detected between SYa4 and SYwt cells, suggesting that the recruitment of ERKs was not affected by the specific downregulation of PKCa. This also suggests that although MAP kinases can be activated by PKC following phorbol ester treatment 33,34 and that such activation may promote sAPPa release, PKCa is not the kinase isoform involved. This is consistent with data in the literature that suggests that PKCe is the only kinase isoform in SK-N-BE2(C) neuroblastoma cells involved in MAP-kinase activation upon m3 muscarinic receptor challenge.…”

Section: Discussionmentioning

confidence: 99%

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Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

et al. 2003

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Protein kinase C (PKC) has a key role in the signal transduction machinery involved in the regulation of amyloid precursor protein (APP) metabolism. Direct and indirect receptor-mediated activation of PKC has been shown to increase the release of soluble APP (sAPPa) and reduce the secretion of b-amyloid peptides. Experimental evidence suggests that specific isoforms of PKC, such as PKCa and PKCe, are involved in the regulation of APP metabolism. In this study, we characterized the role of PKCa in the regulated secretion of APP using wild-type SH-SY5Y neuroblastoma cells and cells transfected with a plasmid expressing PKCa antisense cDNA. Cells expressing antisense PKCa secrete less sAPPa in response to phorbol esters. In contrast, carbachol increases the secretion of sAPPa to similar levels in wild-type cells and in cells transfected with antisense PKCa by acting on APP metabolism through an indirect pathway partially involving the activation of PKC. These results suggest that the direct PKC-dependent activation of the APP secretory pathway is compromised by reduced PKCa expression and a specific role of this isoform in these mechanisms. On the other hand, indirect pathways that are also partially dependent on the mitogen-activated protein kinase signal transduction mechanism remain unaffected and constitute a redundant, compensatory mechanism within the APP secretory pathway.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

et al. 2003

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“…Moreover, the MAPK signaling pathway has recently been implicated in both PKC and tyrosine kinase receptor regulation of APP processing (45,46). We therefore assessed which, if any, of these kinases is involved in mediating the action of NSAIDs on sAPP␣ release using specific signaling inhibitors (Fig.…”

Section: Resultsmentioning

confidence: 99%

Non-steroidal Anti-inflammatory Drugs Stimulate Secretion of Non-amyloidogenic Precursor Protein

Avramovich¹,

Amit²,

Youdim³

2002

Journal of Biological Chemistry

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Chronic inflammatory processes are associated with the pathophysiology of Alzheimer's disease (AD), and it has been proposed that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk for AD. Here we report that various NSAIDs, such as the cyclooxygenase inhibitors, nimesulide, ibuprofen and indomethacin, as well as thalidomide (Thal) and its nonteratogenic analogue, supidimide, significantly stimulated the secretion of the non-amyloidogenic ␣-secretase form of the soluble amyloid precursor protein (sAPP␣) into the conditioned media of SH-SY5Y neuroblastoma and PC12 cells. These NSAIDs markedly reduced the levels of the cellular APP holoprotein, further accelerating non-amyloidogenic processes. sAPP␣ release, induced by nimesulide and Thal, was modulated by inhibitors of protein kinase C and Erk mitogen-activated protein (MAP) kinase. Furthermore, in results complementary to the inhibitor studies, we show for the first time that NSAIDs can activate the Erk MAP kinase signaling cascade, thus identifying a novel pharmacology mechanism of NSAIDs. Our findings suggest that NSAIDs and Thal might prove useful to favor non-amyloidogenic APP processing by enhancing ␣-secretase activity, thereby reducing the formation of amyloidogenic derivatives, and therefore are of potential therapeutic value in AD.Alzheimer's disease (AD) 1 pathology is characterized by senile plaques containing ␤-amyloid peptide (A␤), a protein with neurotoxic and glial immune-activating potential (for review, see Refs 1-3). A␤, a 39 -43 amino acid peptide, is derived from a larger transmembrane glycoprotein, the amyloid precursor protein (APP) (4, 5). APP can be processed proteolytically via alternative pathways; cleavages at the N and C termini of A␤ domain by ␤-and ␥-secretases, respectively, lead to the formation of the A␤ peptide. In addition, in the ␣-secretase pathway, the cleavage occurs within the sequence of A␤ peptide and generates a large, secreted form of soluble APP (sAPP), thus precluding the formation of the amyloidogenic A␤ (for recent reviews of APP processing, see Refs. 6 and 7). Because the proportion of APP processed by ␤-secretase versus ␣-secretase may affect the amount of A␤ produced, the regulation of these two pathways may be critically important to the pathogenesis of AD. Previous studies have demonstrated that sAPP secretion could be enhanced by activation of various cell surface receptors, coupled to increased activation of second messenger cascades, including phosphatidylinositol hydrolysis, tyrosine phosphorylation, protein kinase C (PKC), protein kinase A, mitogen-activated protein kinase (MAPK), protein phosphatase 1 and 2B, and calcium (8).In the search for the pathogenic mechanism of AD, much interest has been focused recently on the involvement of inflammatory reactions in AD. A chronic inflammatory response has been described in the brain of AD patients (9), characterized by the presence of activated astrocytes surrounding the senile plaque and activated microglia surrounding and extendin...

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“…These include the protein kinases PKA, PKC, GSK3-␤, and Cdk5 (3,(30)(31)(32), and the protein phosphatases PP1/PP2A and PP2B (30,33). Early studies demonstrated that activation of PKA or PKC or inhibition of PP1/PP2A or PP2B causes a dramatic reduction in the formation of A␤ and/or an increase in the amount of the ␣-secretase cleavage product sAPP␣ (30).…”

Section: )mentioning

confidence: 99%

Regulation of Alzheimer's disease amyloid-β formation by casein kinase I

Flajolet

He²,

Heiman³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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166

124

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Alzheimer's disease (AD) is associated with accumulation of the neurotoxic peptide amyloid-␤ (A␤), which is produced by sequential cleavage of amyloid precursor protein (APP) by the aspartyl protease ␤-secretase and the presenilin-dependent protease ␥-secretase. An increase of casein kinase 1 (CK1) expression has been described in the human AD brain. We show, by using in silico analysis, that APP, ␤-secretase, and ␥-secretase subunits contain, in their intracellular regions, multiple CK1 consensus phosphorylation sites, many of which are conserved among human, rat, and mouse species. Overexpression of constitutively active CK1, one of the CK1 isoforms expressed in brain, leads to an increase in A␤ peptide production. Conversely, three structurally dissimilar CK1-specific inhibitors significantly reduced endogenous A␤ peptide production. By using mammalian cells expressing the ␤ C-terminal fragment of APP, it was possible to demonstrate that CK1 inhibitors act at the level of ␥-secretase cleavage. Importantly, Notch cleavage was not affected. Our results indicate that CK1 represents a therapeutic target for prevention of A␤ formation in AD.␥-cleavage ͉ neurodegenerative ͉ amyloid precursor protein

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Regulation of Secretion of Alzheimer Amyloid Precursor Protein by the Mitogen‐Activated Protein Kinase Cascade

Cited by 108 publications

References 32 publications

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Non-steroidal Anti-inflammatory Drugs Stimulate Secretion of Non-amyloidogenic Precursor Protein

Regulation of Alzheimer's disease amyloid-β formation by casein kinase I

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