A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings

Nagasaka, Yosuke; Dillner, Karin; Ebise, Hayao; Teramoto, Reiji; Nakagawa, Hiroyuki; Lilius, Lena; Axelman, Karin; Forsell, Charlotte; Itô, Akira; Winblad, Bengt; Kimura, Tōru; Graff, Caroline

doi:10.1073/pnas.0504178102

Cited by 45 publications

(31 citation statements)

References 37 publications

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“…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). Blood lymphocytes were found to be more susceptible to variation introduced by external stimuli such as fever, infections, and drug treatment.…”

Section: Discussionsupporting

confidence: 59%

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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Section: Discussionsupporting

confidence: 59%

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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“…The potential use of bloodbased gene expression profiling in the diagnosis of brain disorders has been described by several independent groups (Burczynski and Dorner, 2006;Sharp et al, 2006). Expression profiling of whole blood RNA offers several advantages in deciphering aberrant patterns of gene regulation in neurodegenerative processes: it might predict much earlier changes than that measured by means of protein 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 mutations showed that mutation carriers share a common gene expression profile significantly different from that of their wild-type siblings (Nagasaka et al, 2005). This suggests that the disease process starts decades before the onset of cognitive decline, and that presymptomatic diagnosis of AD may be feasible in the near future.…”

Section: Genetic Biomarkersmentioning

confidence: 99%

Biomarkers for Alzheimer’s disease and other forms of dementia: Clinical needs, limitations and future aspects

Cedazo-Minguez

Winblad

2010

Experimental Gerontology

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133

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To cite this version:Angel Cedazo-Minguez, Bengt Winblad. Biomarkers for Alzheimer's disease and other forms of dementia: clinical needs, limitations and future aspects. Experimental Gerontology, Elsevier, 2009, 45 (1), pp. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT

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“…Endogenous controls were initially selected based on low inter-sample variability on RNA microarrays with human fibroblast cultures (data not shown), and earlier usage in quantitative RT-PCR experiments on HGPS cell lines. 17,27 The selected endogenous controls, b-glucuronidase, and RPLPO were evaluated on our sample material (n ¼ 67), and the absolute values for estimated copies were compared. Similar expression profiles were obtained with both endogenous controls (data not shown); but as the expression level of b-glucuronidase was closer to the levels of the LMNA locus transcripts, it was used for normalization.…”

Section: Validation Of Taqman Assaysmentioning

confidence: 99%

Increased expression of the Hutchinson–Gilford progeria syndrome truncated lamin A transcript during cell aging

et al. 2009

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Most cases of the segmental progeroid syndrome, Hutchinson -Gilford progeria syndrome (HGPS), are caused by a de novo dominant mutation within a single codon of the LMNA gene. This mutation leads to the increased usage of an internal splice site that generates an alternative lamin A transcript with an internal deletion of 150 nucleotides, called lamin AD150. The LMNA gene encodes two major proteins of the inner nuclear lamina, lamins A and C, but not much is known about their expression levels. Determination of the overall expression levels of the LMNA gene transcripts is an important step to further the understanding of the HGPS. In this study, we have performed absolute quantification of the lamins A, C and AD150 transcripts in primary dermal fibroblasts from HGPS patients and unaffected age-matched and parent controls. We show that the lamin AD150 transcript is present in unaffected controls but its expression is 4160-fold lower than that in samples from HGPS patients. Analysis of transcript expression during in vitro aging shows that although the levels of lamin A and lamin C transcripts remain unchanged, the lamin AD150 transcript increases in late passage cells from HGPS patients and parental controls. This study provides a new method for LMNA transcript analysis and insights into the expression of the LMNA gene in HGPS and normal cells.

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A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings

Cited by 45 publications

References 37 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

Biomarkers for Alzheimer’s disease and other forms of dementia: Clinical needs, limitations and future aspects

Increased expression of the Hutchinson–Gilford progeria syndrome truncated lamin A transcript during cell aging

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