Cytosol protein kinase C downregulation in fibroblasts from Alzheimer's disease patients

Govoni, Stefano; Bergamaschi, S.; Racchi, Marco; Battaini, F.; Binetti, Giuliano; Bianchetti, Angelo; Trabucchi, Marco

doi:10.1212/wnl.43.12.2581

Cited by 107 publications

(60 citation statements)

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“…In addition, data from a number of laboratories, including ours, have demonstrated a decreased PKC activity in sporadic AD fibroblasts. 10 We also observed an increase of the Kd (dissociation constant) for phorbol ester binding in the cytosolic fraction of AD fibroblasts, which suggested an alteration in the characteristics of the kinase. Subsequently, the described changes in PKC were correlated to a specific 30% reduction in PKCa immunoreactivity.…”

Section: Introductionmentioning

confidence: 57%

“…6,7 The extensive studies on regulation of APP processing by PKC suggest that the Ab forming amyloidogenic pathway and the non-amyloidogenic a-secretase pathway are balanced, the latter being activated by PKC. Although this simple view of APP metabolism may not fully reflect the complexity of the system, 22 PKC-defective pathways have been described in peripheral tissues of sporadic AD patients 10,23 and these defects have been associated with aberrant APP processing. 11 The central role of PKC in APP metabolism is therefore also connected to the fact that defective PKC is one of the most consistent findings in AD brain and peripheral tissues.…”

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: Introductionmentioning

confidence: 57%

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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“…Because experiments were performed in a cell-free condition, Ah must have interacted with PKC in a direct manner, and to our knowledge, this is the first demonstration of such a direct interaction between Ah and PKC. Although previous studies have demonstrated degradation of PKC (Favit et al, 1998), reduction of PKC-mediated phosphorylation (Chauhan et al, 1991;Govoni et al, 1993), and decrease of PKCa membrane translocation (Pakaski et al, 2002) by Ah, these studies were performed using cultured cells or a liposome system; thus, it was uncertain whether the effects of Ah were direct or indirect. When deletion (DKGA) or point mutation (GGA) was induced into the putative PKC pseudosubstrate sequence, Ah lost its effects on PKC phosphorylation in the cell-free system, indicating that the putative sequence is indeed responsible for direct Ah -PKC interaction.…”

Section: Discussionmentioning

confidence: 99%

Amyloid beta peptide directly inhibits PKC activation

Lee

Boo

Jung

et al. 2004

Molecular and Cellular Neuroscience

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“…PKC-mediated ␣-secretase activation is responsible for TNF-␣ generation. Furthermore, deficits of PKC isozymes have been found in AD brain tissues (8) and skin fibroblasts (9)(10)(11), as have deficits of PKC-mediated phosphorylation of MAPK (12). Therefore, we investigated a molecular biomarker that assays both MAPK Erk1 and Erk2 phosphorylation in response to the inflammatory signaling molecule bradykinin (BK), which activates PKC pathways.…”

mentioning

confidence: 99%

An internally controlled peripheral biomarker for Alzheimer’s disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin

Khan

Alkon

2006

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

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diagnostic ͉ MAPK ͉ Alzheimer's index ͉ PKC ͉ human fibroblasts R ecent evidence in human patients and animal models supports the hypothesis that early dysfunction in the brains of Alzheimer's disease (AD) patients involves inflammatory signaling pathways. For example, in several studies the cognitive impairment of AD patients increased with changes in two inflammatory signals: lower plasma TNF-␣ levels and higher levels of IL-1␤ (1-7). PKC-mediated ␣-secretase activation is responsible for TNF-␣ generation. Furthermore, deficits of PKC isozymes have been found in AD brain tissues (8) and skin fibroblasts (9-11), as have deficits of PKC-mediated phosphorylation of MAPK (12). Therefore, we investigated a molecular biomarker that assays both MAPK Erk1 and Erk2 phosphorylation in response to the inflammatory signaling molecule bradykinin (BK), which activates PKC pathways.The neurodegenerative processes responsible for AD may begin well before the disease can be detected by current clinical and͞or imaging diagnostic criteria. Therefore, a biological marker to predict or confirm AD would be invaluable for initiating early therapeutic regimens (13,14). Although definitive diagnosis of AD requires both clinically demonstrated dementia and amyloid plaques and tangles at autopsy, a molecular marker in peripheral tissue (e.g., skin, blood, and saliva) with high sensitivity and specificity, detectable soon after the onset of symptoms, could be important for enhancing the accuracy of clinical diagnosis and screening AD drug therapies.Recently, several studies have suggested that AD may indeed have systemic manifestations caused by molecular͞biophysical changes early in disease progression (15)(16)(17). AD skin fibroblast cell lines, for example, may offer a cellular environment in which the effects of AD-specific differences in amyloid ␤ (A␤)(1-42) have altered signal transduction. Such studies have identified AD-specific changes in K ϩ channels that are also sensitive to A␤(1-42) interaction (15), changes in BK-mediated calcium mobilization via the IP 3 receptor (16), and changes in MAPK phosphor ylation (12). Still another report documented differences in A␤ secretion from skin fibroblasts of family members with familial AD genes (17).BK is a potent inflammatory mediator that is produced in both brain and peripheral cells (e.g., skin fibroblasts) under pathophysiological conditions such as trauma, stroke, ischemia, and asthma. Via the G-protein-coupled B2 BK receptor (BK2bR), BK activates the phospholipase C͞phospholipid-Ca 2ϩ ͞PKC cascade that, in turn, interacts with the Ras͞Raf͞MAPK kinase͞ MAPK signaling pathway, ultimately causing Erk1͞2 phosphorylation (18). Erk1 and Erk2 were previously reported to be activated in response to A␤ stimulation of the MAPK signaling pathways (19). Here, we introduce an Alzheimer's Erk1 and Erk2 index that differentially compares Erk1 and Erk2 phosphorylation induced by BK application within the media bathing human skin fibroblasts. The results, obtained by using both fibroblasts from ...

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Cytosol protein kinase C downregulation in fibroblasts from Alzheimer's disease patients

Cited by 107 publications

References 0 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

Amyloid beta peptide directly inhibits PKC activation

An internally controlled peripheral biomarker for Alzheimer’s disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin

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