CSF proteome: a protein repository for potential biomarker identification

Romeo, Martin J.; Espina, Virginia; Lowenthal, Mark S.; Espina, Benjamin H.; Petricoin, Emanuel F.; Liotta, Lance A.

doi:10.1586/14789450.2.1.57

Cited by 115 publications

(63 citation statements)

References 104 publications

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“…Among the six subjects, comparison between the four cognitively normal and the two very mildly demented subjects also yielded some proteins that have been identified in previous AD biomarker studies. These results validate our method of identifying differences in proteomic profiles of CSF samples and have important implications for the de Cerebrospinal fluid (CSF) 1 is produced mainly by the choroid plexus within the ventricles of the brain. It circulates through the ventricular system and around the outside of the brain and spinal cord in the subarachnoid space.…”

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confidence: 65%

Comparative Proteomic Analysis of Intra- and Interindividual Variation in Human Cerebrospinal Fluid

Malone

Fagan

et al. 2005

Molecular & Cellular Proteomics

114

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Cerebrospinal fluid (CSF) is a potential source of biomarkers for many disorders of the central nervous system, including Alzheimer disease (AD). Prior to comparing CSF samples between individuals to identify patterns of disease-associated proteins, it is important to examine variation within individuals over a short period of time so that one can better interpret potential changes in CSF between individuals as well as changes within a given individual over a longer time span. In this study, we analyzed 12 CSF samples, composed of pairs of samples from six individuals, obtained 2 weeks apart. Multiaffinity depletion, two-dimensional DIGE, and tandem mass spectrometry were used. A number of proteins whose abundance varied between the two time points was identified for each individual. Some of these proteins were commonly identified in multiple individuals. More importantly, despite the intraindividual variations, hierarchical clustering and multidimensional scaling analysis of the proteomic profiles revealed that two CSF samples from the same individual cluster the closest together and that the between-subject variability is much larger than the within-subject variability. Among the six subjects, comparison between the four cognitively normal and the two very mildly demented subjects also yielded some proteins that have been identified in previous AD biomarker studies. These results validate our method of identifying differences in proteomic profiles of CSF samples and have important implications for the design of CSF biomarker studies for AD and other central nervous system disorders. Cerebrospinal fluid (CSF) 1 is produced mainly by the choroid plexus within the ventricles of the brain. It circulates through the ventricular system and around the outside of the brain and spinal cord in the subarachnoid space. CSF is clinically accessible through standard lumbar puncture techniques. Because it is in direct contact with the brain interstitial fluid, biochemical changes taking place in the brain are often reflected in CSF. These features make CSF potentially a very useful source of biomarkers for diagnosis and response to treatment as well as for providing information on pathological processes underlying a number of central nervous system disorders, including Alzheimer disease (AD) (for reviews, see Refs. 1 and 2). Based on known pathology and the hypothesized etiology of AD, a few AD biomarkers in CSF have been identified that may differentiate groups of individuals with clinical disease from those who are cognitively normal, including amyloid ␤ (A␤) 42, total tau, phospho-tau, isoprostane, and sulfatide (3-7). Although some candidate biomarkers have shown promise, each has its limitations. Researchers are still searching for biomarkers that have a higher sensitivity and specificity to differentiate AD from normal aging and other dementias, especially in the early stages. It would also be especially useful to develop antecedent biomarkers for AD, considering its estimated preclinical phase of 10 -20 years (8).Ne...

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supporting

confidence: 65%

Comparative Proteomic Analysis of Intra- and Interindividual Variation in Human Cerebrospinal Fluid

Malone

Fagan

et al. 2005

Molecular & Cellular Proteomics

114

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“…All authors have given approval to the final version of the manuscript. 1 The abbreviations used are: CSF, cerebrospinal fluid; APP, amyloid precursor protein; BACE1, ␤-site APP cleaving enzyme 1; FASP, filter aided sample preparation; FDR, false discovery rate; iBAQ, intensity based absolute quantification; LFQ, label-free quantification. …”

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confidence: 99%

Label-free Quantitative Proteomics of Mouse Cerebrospinal Fluid Detects β-Site APP Cleaving Enzyme (BACE1) Protease Substrates In Vivo

Dislich

Wohlrab

Bachhuber

et al. 2015

Molecular & Cellular Proteomics

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Analysis of murine cerebrospinal fluid (CSF) by quantitative mass spectrometry is challenging because of low CSF volume, low total protein concentration, and the presence of highly abundant proteins such as albumin. We demonstrate that the CSF proteome of individual mice can be analyzed in a quantitative manner to a depth of several hundred proteins in a robust and simple workflow consisting of single ultra HPLC runs on a benchtop mass spectrometer. The workflow is validated by a comparative analysis of BACE1؊/؊ and wild-type mice using label-free quantification. The protease BACE1 cleaves the amyloid precursor protein (APP) as well as several other substrates and is a major drug target in Alzheimer's disease. We identified a total of 715 proteins with at least 2 unique peptides and quantified 522 of those proteins in CSF from BACE1؊/؊ and wild-type mice. Several proteins, including the known BACE1 substrates APP, APLP1, CHL1 and contactin-2 showed lower abundance in the CSF of BACE1؊/؊ mice, demonstrating that BACE1 substrate identification is possible from CSF. Additionally, ectonucleotide pyrophosphatase 5 was identified as a novel BACE1 substrate and validated in cells using immunoblots and by an in vitro BACE1 protease assay. Likewise, receptor-type tyrosine-protein phosphatase N2 and plexin domain-containing 2 were confirmed as BACE1 substrates by in vitro assays. Taken Cerebrospinal fluid (CSF) 1 consists of interstitial fluid that is in continuous exchange with the central nervous system and the peripheral blood system. It represents the only body fluid in humans that is in direct contact with brain tissue and accessible in a routine clinical setting. Thus, the easy accessibility from the periphery renders CSF perfectly suited to study pathologic neurological processes (1). Human CSF has a relatively low protein content (ϳ 0.4 mg/ml), but features a highly diverse proteome. It is thus increasingly studied by modern mass spectrometry based proteomics (2). The proteomic analysis of human CSF typically involves various protein concentration and fractionation steps as well as the depletion of highly abundant proteins, such as serum albumin. This allows the identification of several hundred up to 2600 proteins from several milliliters of human CSF (3).Mice are the most popular animal model in preclinical research, because of their similarity to humans in genetics and physiology, their unlimited supply and their ease of genetic engineering. The study of their CSF can provide valuable insights into disease mechanisms and biomarker discovery Author Contributions: The manuscript was written by Bastian Dislich and Stefan F. Lichtenthaler. The study was guided and planned by Bastian Dislich, Sebastian Hogl, Melanie Meyer-Luehmann and Stefan F. Lichtenthaler. Bastian Dislich established the mass spectrometry of murine CSF and performed the proteomic analysis of the BACE1Ϫ/Ϫ CSF. Felix Wohlrab performed all other experiments, except for the CSF extraction, which was performed by Teresa Bachhuber, and the analysis of...

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“…It is in close contact with the extracellular fluid of the brain. Therefore, the composition of CSF can reflect biological processes of the brain (4). By discovering the characterization of the proteome and metabolome of CSF we may gain better insight on the pathogenesis of CNS disorders.…”

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confidence: 99%

Quantitative Proteomics and Metabolomics Analysis of Normal Human Cerebrospinal Fluid Samples*

Stoop¹,

Coulier

Rosenling

et al. 2010

Molecular & Cellular Proteomics

129

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CSF proteome: a protein repository for potential biomarker identification

Cited by 115 publications

References 104 publications

Comparative Proteomic Analysis of Intra- and Interindividual Variation in Human Cerebrospinal Fluid

Comparative Proteomic Analysis of Intra- and Interindividual Variation in Human Cerebrospinal Fluid

Label-free Quantitative Proteomics of Mouse Cerebrospinal Fluid Detects β-Site APP Cleaving Enzyme (BACE1) Protease Substrates In Vivo

Quantitative Proteomics and Metabolomics Analysis of Normal Human Cerebrospinal Fluid Samples*

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