Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease

Gasparini, Laura; Racchi, Marco; Binetti, Giuliano; Trabucchi, Marco; Solerte, Sebastiano Bruno; Alkon, Daniel L.; Etcheberrigaray, René; Gibson, Gary E.; Blass, John P.; Paoletti, Rodolfo; Govoni, Stefano

doi:10.1096/fasebj.12.1.17

Cited by 149 publications

(84 citation statements)

References 203 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This systemic pathophysiologic view of AD is consistent with recent observations that amyloid and tau metabolic pathways are ubiquitous in the human body and are manifest in blood, saliva, skin, and extra-brain tissues (21). Among the peripheral tissues, the superiority of skin fibroblasts over peripheral blood lymphocytes was recently discussed in a gene expression study for familial AD cases (22).…”

Section: Discussionsupporting

confidence: 85%

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.

View full text Add to dashboard Cite

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 ...

show abstract

Section: Discussionsupporting

confidence: 85%

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.

View full text Add to dashboard Cite

show abstract

“…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. 8,24 In our previous work, we found that the defective APP metabolism described in AD fibroblasts is paralleled by a defective PKC activity and, in particular, PKCa was found to be reduced in AD fibroblasts. 11 The average reduction in the expression of PKCa protein in AD fibroblasts was 30%, similar to the levels of down-regulation of approximately 40% observed in the SYa4 neuroblastoma cellular model used in this study.…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2003

View full text Add to dashboard Cite

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.

show abstract

“…Senile plaques are characterized by the accumulation of proteins in the form of -pleated sheet fibrils, which are composed mainly of a 42 amino acids peptide known as -amyloid (A ) [36]. In particular, the "amyloid cascade hypothesis" supports the idea that A is the main pathogenetic factor of AD because the aberrant metabolism of the amyloid precursor protein and the subsequent massive production and deposition of the peptide in extracellular sites are responsible for a concatenate series of events that have as a final result neurotoxicity and consequent neuronal death [37,38].…”

Section: Neurodegenerationmentioning

confidence: 96%

Low Grade Inflammation as a Common Pathogenetic Denominator in Age-Related Diseases: Novel Drug Targets for Anti-Ageing Strategies and Successful Ageing Achievement

Candore

Caruso

Jirillo³

et al. 2010

CPD

118

View full text Add to dashboard Cite

Nowadays, people are living much longer than they used to do, however they are not free from ageing. Ageing, an inexorable intrinsic process that affects all cells, tissues, organs and individuals, is a post-maturational process that, due to a diminished homeostasis and increased organism frailty, causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. However, the high incidence of death due to infectious, cardiovascular and cancer diseases underlies a common feature in these pathologies that is represented by dysregulation of both instructive and innate immunity. Several studies show that a low-grade systemic inflammation characterizes ageing and that inflammatory markers are significant predictors of mortality in old humans. This pro-inflammatory status of the elderly underlies biological mechanisms responsible for physical function decline and agerelated diseases such as Alzheimer's disease and atherosclerosis are initiated or worsened by systemic inflammation. Understanding of the ageing process should have a prominent role in new strategies for extending the health old population. Accordingly, as extensively discussed in the review and in the accompanying related papers, investigating ageing pathophysiology, particularly disentangling agerelated low grade inflammation, is likely to provide important clues about how to develop drugs that can slow or delay ageing.

show abstract

Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease

Cited by 149 publications

References 203 publications

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

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

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

Low Grade Inflammation as a Common Pathogenetic Denominator in Age-Related Diseases: Novel Drug Targets for Anti-Ageing Strategies and Successful Ageing Achievement

Contact Info

Product

Resources

About