Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease.
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3792042?pdf=render |
| _version_ | 1818480737668562944 |
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| author | Jere E Meredith 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 |
| author_facet | Jere E Meredith 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 |
| author_sort | Jere E Meredith |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T11:26:22Z |
| format | Article |
| id | doaj.art-1cf423c06b374b6aa3a7e3df8f786b15 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T11:26:22Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1cf423c06b374b6aa3a7e3df8f786b152022-12-22T01:50:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01810e7652310.1371/journal.pone.0076523Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease.Jere E MeredithSethu SankaranarayananValerie GussAnthony J LanzettiFlora BerishaRobert J NeelyJ Randall SlemmonErik PorteliusHenrik ZetterbergKaj BlennowHolly SoaresMichael AhlijanianCharles F AlbrightCerebral 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.http://europepmc.org/articles/PMC3792042?pdf=render |
| spellingShingle | Jere E Meredith 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 Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease. PLoS ONE |
| title | Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease. |
| title_full | Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease. |
| title_fullStr | Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease. |
| title_full_unstemmed | Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease. |
| title_short | Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease. |
| title_sort | characterization of novel csf tau and ptau biomarkers for alzheimer s disease |
| url | http://europepmc.org/articles/PMC3792042?pdf=render |
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