Proteomic analysis of peripheral leukocytes in Alzheimer's disease patients treated with divalproex sodium

Center for Aging and Developmental Biology, Aab Institute for Biomedical Research, University of Rochester School of Medicine and Dentistry, Box 645, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Neurobiology of aging (Impact Factor: 5.01). 06/2007; 29(11):1631-43. DOI: 10.1016/j.neurobiolaging.2007.04.004
Source: PubMed


The molecular profiling of peripheral tissues, including circulating leukocytes, may hold promise in the discovery of biomarkers for diagnosing and treating neurodegenerative diseases, including Alzheimer's disease (AD). As a proof-of-concept, we performed a proteomics study on peripheral leukocytes from patients with AD both before and during treatment with divalproex sodium. Using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, we identified 10 differentially expressed proteins: two up-regulated proteins, 14-3-3 protein epsilon and peroxiredoxin 2; and eight down-regulated proteins, actin-interacting protein, mitogen activated protein kinase 1, beta actin, annexin A1, glyceraldehyde 3-phosphate dehydrogenase, transforming protein RhoA, acidic leucine-rich nuclear phosphoprotein 32 family member B, and a currently unidentified protein. A subset was validated on both the transcript and protein levels in normal human peripheral blood mononuclear cell cultures treated with valproic acid. These proteins comprise a number of functional classes that may be important to the biology of AD and to the therapeutic action of valproate. These data also suggest the potential of using peripheral leukocytes to monitor pharmaceutical action for neurodegenerative diseases.

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    • "94 Plasma 2D-GE LC/MS/MS AD versus CTL Henkel Henkel et al. [38] 14 Plasma Immunodepletion and Difference GE AD versus CTL Hu Hu et al. [41] 230 Plasma Myriad RBM -Luminex xMAP Associated with mild dementia/MCI/AD Liao Liao et al. [33] 20 Plasma 2D-GE MS AD versus CTL Liu Liu et al. [32] 133 Serum 2D-GE MALDI-TOF MS AD versus CTL Mhyre Mhyre et al. [36] 15 Plasma 2D-GE MALDI-TOF MS Markers of AD drug efficacy Ray Ray et al. [7] "
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    ABSTRACT: A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of AD would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (>100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: α-1-antitrypsin, α-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value <0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency.
    Journal of Alzheimer's disease: JAD 10/2013; 38(3). DOI:10.3233/JAD-130380 · 4.15 Impact Factor
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    • "Two widely used mood stabilizers, lithium and valproate, are also inhibitors of this enzyme, reducing tau phosphorylation in animal models61. Proteomic studies in AD patients treated with valproate indicated ten differentially expressed proteins related to functional classes implicated in the neurobiology of the disease and to the therapeutic action of drug62. However, in a multicenter clinical trial conducted by the Alzheimer's Disease Cooperative Study (ADCS), an accelerated decrease in total brain and hippocampal volume was observed after 1 year of followup among patients treated with divalproex sodium, which was accompanied by greater cognitive impairment63. "
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    The Indian Journal of Medical Research 10/2013; 138(4):449-60. · 1.40 Impact Factor
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    PLoS ONE 02/2012; 7(2):e30512. DOI:10.1371/journal.pone.0030512 · 3.23 Impact Factor
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