Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer’s Disease
Publication Date
October 07, 2013
Journal
PLOS ONE
Authors
Jere E. Meredith Jr., Sethu Sankaranarayanan, Valerie Guss, Anthony J. Lanzetti, et al
Volume
8
Issue
10
Pages
e76523
DOI
https://dx.plos.org/10.1371/journal.pone.0076523
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0076523
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24116116
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792042
Europe PMC
http://europepmc.org/abstract/MED/24116116
Web of Science
000325501300063
Scopus
84885041658
Mendeley
http://www.mendeley.com/research/characterization-novel-csf-tau-ptau-biomarkers-alzheimers-disease
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Mendeley | Further Information

{"title"=>"Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer's Disease", "type"=>"journal", "authors"=>[{"first_name"=>"Jere E.", "last_name"=>"Meredith", "scopus_author_id"=>"55240587600"}, {"first_name"=>"Sethu", "last_name"=>"Sankaranarayanan", "scopus_author_id"=>"8347198400"}, {"first_name"=>"Valerie", "last_name"=>"Guss", "scopus_author_id"=>"6506057201"}, {"first_name"=>"Anthony J.", "last_name"=>"Lanzetti", "scopus_author_id"=>"6602511561"}, {"first_name"=>"Flora", "last_name"=>"Berisha", "scopus_author_id"=>"55874438100"}, {"first_name"=>"Robert J.", "last_name"=>"Neely", "scopus_author_id"=>"56609973000"}, {"first_name"=>"J. Randall", "last_name"=>"Slemmon", "scopus_author_id"=>"6603768077"}, {"first_name"=>"Erik", "last_name"=>"Portelius", "scopus_author_id"=>"12806782700"}, {"first_name"=>"Henrik", "last_name"=>"Zetterberg", "scopus_author_id"=>"6701454676"}, {"first_name"=>"Kaj", "last_name"=>"Blennow", "scopus_author_id"=>"55171296400"}, {"first_name"=>"Holly", "last_name"=>"Soares", "scopus_author_id"=>"35241097600"}, {"first_name"=>"Michael", "last_name"=>"Ahlijanian", "scopus_author_id"=>"6603829161"}, {"first_name"=>"Charles F.", "last_name"=>"Albright", "scopus_author_id"=>"7102026458"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"369965523", "sgr"=>"84885041658", "pmid"=>"24116116", "scopus"=>"2-s2.0-84885041658", "isbn"=>"10.1371/journal.pone.0076523", "doi"=>"10.1371/journal.pone.0076523", "issn"=>"19326203"}, "id"=>"59196834-a4cc-3eb4-b052-e44e428399c2", "abstract"=>"Cerebral spinal fluid (CSF) Aβ42, tau and p181tau are widely accepted biomarkers of Alzheimer's disease (AD). Numerous studies show that CSF tau and p181tau levels are elevated in mild-to-moderate AD compared to age-matched controls. In addition, these increases might predict preclinical AD in cognitively normal elderly. Despite their importance as biomarkers, the molecular nature of CSF tau and ptau is not known. In the current study, reverse-phase high performance liquid chromatography was used to enrich and concentrate tau prior to western-blot analysis. Multiple N-terminal and mid-domain fragments of tau were detected in pooled CSF with apparent sizes ranging from <20 kDa to ~40 kDa. The pattern of tau fragments in AD and control samples were similar. In contrast, full-length tau and C-terminal-containing fragments were not detected. To quantify levels, five tau ELISAs and three ptau ELISAs were developed to detect different overlapping regions of the protein. The discriminatory potential of each assay was determined using 20 AD and 20 age-matched control CSF samples. Of the tau ELISAs, the two assays specific for tau containing N-terminal sequences, amino acids 9-198 (numbering based on tau 441) and 9-163, exhibited the most significant differences between AD and control samples. In contrast, CSF tau was not detected with an ELISA specific for a more C-terminal region (amino acids 159-335). Significant discrimination was also observed with ptau assays measuring amino acids 159-p181 and 159-p231. Interestingly, the discriminatory potential of p181 was reduced when measured in the context of tau species containing amino acids 9-p181. Taken together, these results demonstrate that tau in CSF occurs as a series of fragments and that discrimination of AD from control is dependent on the subset of tau species measured. These assays provide novel tools to investigate CSF tau and ptau as biomarkers for other neurodegenerative diseases.", "link"=>"http://www.mendeley.com/research/characterization-novel-csf-tau-ptau-biomarkers-alzheimers-disease", "reader_count"=>96, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>27, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>22, "Student > Postgraduate"=>5, "Student > Master"=>15, "Other"=>12, "Student > Bachelor"=>4, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>27, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>22, "Student > Postgraduate"=>5, "Student > Master"=>15, "Other"=>12, "Student > Bachelor"=>4, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Biochemistry, Genetics and Molecular Biology"=>8, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>33, "Medicine and Dentistry"=>14, "Neuroscience"=>21, "Pharmacology, Toxicology and Pharmaceutical Science"=>5, "Business, Management and Accounting"=>1, "Chemistry"=>4, "Social Sciences"=>2, "Decision Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>14}, "Neuroscience"=>{"Neuroscience"=>21}, "Chemistry"=>{"Chemistry"=>4}, "Social Sciences"=>{"Social Sciences"=>2}, "Decision Sciences"=>{"Decision Sciences"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>33}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>6}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>5}}, "reader_count_by_country"=>{"United States"=>1, "Australia"=>1, "Spain"=>1}, "group_count"=>5}

CrossRef

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1227173"], "description"=>"<p>Human control and AD CSF subjected to RP-HPLC, fractions collected and run on SDS-PAGE gels followed by western-blotting with different tau antibodies. A) HT7 (mid domain antibody). B) Tau 12 (N-terminal antibody). C) K9JA (C-terminal microtubule repeat domain antibody). D) IgG1 isotype control. On each blot, human recombinant tau441 (tau) is included in lane 1 and molecular weight markers (mw) in lane 2 followed by the HPLC fractions from 1 to 6 or HPLC fractions 7 to 11. Fractions 1 and 2 were pooled and run as a single sample, while fractions 3-10 were run as individual samples. Control CSF (C) and AD CSF (D) samples for each fraction were run side by side for comparison.</p>", "links"=>[], "tags"=>["tau", "fragments"], "article_id"=>816564, "categories"=>["Biological Sciences"], "users"=>["Jere E. Meredith Jr.", "Sethu Sankaranarayanan", "Valerie Guss", "Anthony J. Lanzetti", "Flora Berisha", "Robert J. Neely", "J. Randall Slemmon", "Erik Portelius", "Henrik Zetterberg", "Kaj Blennow", "Holly Soares", "Michael Ahlijanian", "Charles F. Albright"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076523.g001", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Detection_of_tau_fragments_in_human_CSF_/816564", "title"=>"Detection of tau fragments in human CSF.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-07 02:20:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1227174"], "description"=>"<p>Schematic of tau 441 protein with the approximate location of various linear epitope antibodies Tau12, HT7, BT2, Tau5, AT120 and 77G7 and phospho-site specific antibodies AT270 (p181) and PHF6 (p231) indicated; additional antibody epitope and clone information included in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076523#pone-0076523-t001\" target=\"_blank\">Table 1</a>. Antibody combinations used for the different tau and ptau ELISAs are shown. For each assay, capture antibodies are highlighted in red, detection antibodies in black and the minimal tau region required (aa numbering based on tau 441) is indicated. Antibodies used in the INNOTEST/INNO-BIA AlzBio3 total tau and p181 tau assays are also shown for comparison.</p>", "links"=>[], "tags"=>["ptau"], "article_id"=>816565, "categories"=>["Biological Sciences"], "users"=>["Jere E. Meredith Jr.", "Sethu Sankaranarayanan", "Valerie Guss", "Anthony J. Lanzetti", "Flora Berisha", "Robert J. Neely", "J. Randall Slemmon", "Erik Portelius", "Henrik Zetterberg", "Kaj Blennow", "Holly Soares", "Michael Ahlijanian", "Charles F. Albright"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076523.g002", "stats"=>{"downloads"=>3, "page_views"=>34, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tau_and_ptau_ELISAs_/816565", "title"=>"Tau and ptau ELISAs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-07 02:20:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1227176"], "description"=>"<p>Representative tau 441 standard curves (left panels) and CSF dilution linearity results (right panels) shown for A) HT7-BT2, B) HT7-Tau5, C) Tau12-BT2 and D) Tau12-HT7 tau ELISAs. On each standard curve graph, tau 441 calibrators (Standards) and results for CSF sample dilutions (Samples) are shown. The assay lower limit of quantitation (LLQ, vertical dashed line) is also indicated. On each dilution linearity graph, dilution-corrected tau levels for a pooled control CSF sample and a pooled AD CSF sample relative to sample dilution are shown. The vertical dashed lines indicate the dilution determined to be optimal for CSF analysis.</p>", "links"=>[], "tags"=>["tau"], "article_id"=>816567, "categories"=>["Biological Sciences"], "users"=>["Jere E. Meredith Jr.", "Sethu Sankaranarayanan", "Valerie Guss", "Anthony J. Lanzetti", "Flora Berisha", "Robert J. Neely", "J. Randall Slemmon", "Erik Portelius", "Henrik Zetterberg", "Kaj Blennow", "Holly Soares", "Michael Ahlijanian", "Charles F. Albright"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076523.g003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_tau_ELISAs_/816567", "title"=>"Characterization of tau ELISAs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-07 02:20:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1227177"], "description"=>"<p>Representative tau 441 standard curve (left panel) and CSF dilution linearity results (right panel) shown. On the standard curve graph, tau 441 calibrators (Standards) and results for CSF sample dilutions (Samples) are shown. The assay lower limit of quantitation (LLQ, vertical dashed line) is also indicated. On the dilution linearity graph, tau levels for a pooled control and pooled AD CSF samples tested with or without a 100 pg/ml tau 441 spike are shown.</p>", "links"=>[], "tags"=>["tau"], "article_id"=>816568, "categories"=>["Biological Sciences"], "users"=>["Jere E. Meredith Jr.", "Sethu Sankaranarayanan", "Valerie Guss", "Anthony J. Lanzetti", "Flora Berisha", "Robert J. Neely", "J. Randall Slemmon", "Erik Portelius", "Henrik Zetterberg", "Kaj Blennow", "Holly Soares", "Michael Ahlijanian", "Charles F. Albright"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076523.g004", "stats"=>{"downloads"=>7, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_HT7_77G7_tau_ELISA_/816568", "title"=>"Characterization of HT7+77G7 tau ELISA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-07 02:20:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1227178"], "description"=>"<p>Representative ptau standard curves (left panels) and CSF dilution linearity results (right panels) shown for A) HT7-AT270, B) HT7-PHF6, and C) Tau12-AT270 ptau ELISAs. On each standard curve graph, ptau calibrators (Standards) and results for CSF sample dilutions (Samples) are shown. The assay lower limit of quantitation (LLQ, vertical dashed line) is also indicated. On each dilution linearity graph, dilution-corrected ptau levels for a pooled control and a pooled AD CSF samples relative to sample dilution are shown. The vertical dashed lines indicate the dilution determined to be optimal for CSF analysis.</p>", "links"=>[], "tags"=>["ptau"], "article_id"=>816569, "categories"=>["Biological Sciences"], "users"=>["Jere E. Meredith Jr.", "Sethu Sankaranarayanan", "Valerie Guss", "Anthony J. Lanzetti", "Flora Berisha", "Robert J. Neely", "J. Randall Slemmon", "Erik Portelius", "Henrik Zetterberg", "Kaj Blennow", "Holly Soares", "Michael Ahlijanian", "Charles F. Albright"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076523.g005", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_ptau_assays_/816569", "title"=>"Characterization of ptau assays.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-07 02:20:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1227180"], "description"=>"<p>A set of 20 AD and 20 age-matched normal control CSF samples were analyzed using the tau ELISAs (HT7-BT2, HT7-Tau5, Tau12-BT2, Tau12-HT7 and HT7-77G7) and pTau ELISAs (HT7-AT270, HT7-PHF6 and Tau12-AT270). Dashed lines indicate the assay LLQ corrected for CSF dilution. Statistics based on 2-tailed Student’s t test comparison of log-transformed data, * p < 0.05; ** p< 0.01; *** p < 0.001. </p>", "links"=>[], "tags"=>["ptau", "20", "csf"], "article_id"=>816571, "categories"=>["Biological Sciences"], "users"=>["Jere E. Meredith Jr.", "Sethu Sankaranarayanan", "Valerie Guss", "Anthony J. Lanzetti", "Flora Berisha", "Robert J. Neely", "J. Randall Slemmon", "Erik Portelius", "Henrik Zetterberg", "Kaj Blennow", "Holly Soares", "Michael Ahlijanian", "Charles F. Albright"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0076523.g006", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tau_and_ptau_levels_in_20_AD_and_20_control_CSF_samples_/816571", "title"=>"Tau and ptau levels in 20 AD and 20 control CSF samples.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-07 02:20:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1227183", "https://ndownloader.figshare.com/files/1227184", "https://ndownloader.figshare.com/files/1227185", "https://ndownloader.figshare.com/files/1227186", "https://ndownloader.figshare.com/files/1227187", "https://ndownloader.figshare.com/files/1227188", "https://ndownloader.figshare.com/files/1227189", "https://ndownloader.figshare.com/files/1227190", "https://ndownloader.figshare.com/files/1227191", "https://ndownloader.figshare.com/files/1227192", "https://ndownloader.figshare.com/files/1227193", "https://ndownloader.figshare.com/files/1227194", "https://ndownloader.figshare.com/files/1227195"], "description"=>"<div><p>Cerebral spinal fluid (CSF) Aβ42, tau and p181tau are widely accepted biomarkers of Alzheimer’s disease (AD). Numerous studies show that CSF tau and p181tau levels are elevated in mild-to-moderate AD compared to age-matched controls. In addition, these increases might predict preclinical AD in cognitively normal elderly. Despite their importance as biomarkers, the molecular nature of CSF tau and ptau is not known. In the current study, reverse-phase high performance liquid chromatography was used to enrich and concentrate tau prior to western-blot analysis. Multiple N-terminal and mid-domain fragments of tau were detected in pooled CSF with apparent sizes ranging from <20 kDa to ~40 kDa. The pattern of tau fragments in AD and control samples were similar. In contrast, full-length tau and C-terminal-containing fragments were not detected. To quantify levels, five tau ELISAs and three ptau ELISAs were developed to detect different overlapping regions of the protein. The discriminatory potential of each assay was determined using 20 AD and 20 age-matched control CSF samples. Of the tau ELISAs, the two assays specific for tau containing N-terminal sequences, amino acids 9-198 (numbering based on tau 441) and 9-163, exhibited the most significant differences between AD and control samples. In contrast, CSF tau was not detected with an ELISA specific for a more C-terminal region (amino acids 159-335). Significant discrimination was also observed with ptau assays measuring amino acids 159-p181 and 159-p231. Interestingly, the discriminatory potential of p181 was reduced when measured in the context of tau species containing amino acids 9-p181. Taken together, these results demonstrate that tau in CSF occurs as a series of fragments and that discrimination of AD from control is dependent on the subset of tau species measured. These assays provide novel tools to investigate CSF tau and ptau as biomarkers for other neurodegenerative diseases.</p> </div>", "links"=>[], "tags"=>["csf", "tau", "ptau", "biomarkers"], "article_id"=>816574, "categories"=>["Biological Sciences"], "users"=>["Jere E. Meredith Jr.", "Sethu Sankaranarayanan", "Valerie Guss", "Anthony J. Lanzetti", "Flora Berisha", "Robert J. Neely", "J. Randall Slemmon", "Erik Portelius", "Henrik Zetterberg", "Kaj Blennow", "Holly Soares", "Michael Ahlijanian", "Charles F. Albright"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0076523.s001", "https://dx.doi.org/10.1371/journal.pone.0076523.s002", "https://dx.doi.org/10.1371/journal.pone.0076523.s003", "https://dx.doi.org/10.1371/journal.pone.0076523.s004", "https://dx.doi.org/10.1371/journal.pone.0076523.s005", "https://dx.doi.org/10.1371/journal.pone.0076523.s006", "https://dx.doi.org/10.1371/journal.pone.0076523.s007", "https://dx.doi.org/10.1371/journal.pone.0076523.s008", "https://dx.doi.org/10.1371/journal.pone.0076523.s009", "https://dx.doi.org/10.1371/journal.pone.0076523.s010", "https://dx.doi.org/10.1371/journal.pone.0076523.s011", "https://dx.doi.org/10.1371/journal.pone.0076523.s012", "https://dx.doi.org/10.1371/journal.pone.0076523.s013"], "stats"=>{"downloads"=>108, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_Novel_CSF_Tau_and_ptau_Biomarkers_for_Alzheimer_8217_s_Disease_/816574", "title"=>"Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer’s Disease", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-07 02:20:13"}

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Relative Metric

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