title: An enzyme-generated fragment of tau measured in serum shows an inverse correlation to cognitive function.
abstract: OBJECTIVE
  Alzheimer's disease (AD) is a devastating neurological disease characterized by pathological proteolytic cleavage of tau protein, which appears to initiate death of the neurons. The objective of this study was to investigate whether a proteolytic fragment of the tau protein could serve as blood-based biomarker of cognitive function in AD.
  
  
  METHODS
  We developed a highly sensitive ELISA assay specifically detecting an A Disintegrin and Metalloproteinase 10 (ADAM10)-generated fragment of tau (Tau-A). We characterized the assay in detail with to respect specificity and reactivity in healthy human serum. We used samples from the Tg4510 tau transgenic mice, which over-express the tau mutant P301L and exhibit a tauopathy with similarities to that observed in AD. We used serum samples from 21 well-characterized Alzheimer's patients, and we correlated the Tau-A levels to cognitive function.
  
  
  RESULTS
  The Tau-A ELISA specifically detected the cleavage sequence at the N-terminus of a fragment of tau generated by ADAM10 with no cross-reactivity to intact tau or brain extracts. In brain extracts from Tg4510 mice compared to wt controls we found 10-fold higher levels of Tau-A (p<0.001), which indicates a pathological relevance of this marker. In serum from healthy individuals we found robust and reproducible levels of Tau-A, indicating that the analyte is present in serum. In serum from AD patients an inverse correlation (R² = 0.46, p<0.001) between the cognitive assessment score (Mattis Dementia Rating Scale (MDRS)) and Tau-A levels was observed.
  
  
  CONCLUSIONS
  Based on the hypothesis that tau is cleaved proteolytically and then released into the blood, we here provide evidence for the presence of an ADAM10-generated tau fragment (Tau-A) in serum. In addition, the levels of Tau-A showed an inverse correlation to cognitive function, which could indicate that this marker is a serum marker with pathological relevance for AD.
authors.affiliation: Nordic Bioscience Biomarkers and Research, Herlev, Denmark. kh@nordicbioscience.com
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
authors.forename: Yaguo
authors.initials: Y
authors.lastname: Wang
authors.forename: Mette G
authors.initials: MG
authors.lastname: Sørensen
authors.forename: Natasha
authors.initials: N
authors.lastname: Barascuk
authors.forename: Joyce
authors.initials: J
authors.lastname: Suhy
authors.forename: Jan T
authors.initials: JT
authors.lastname: Pedersen
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Duffin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dean
authors.forename: Monika
authors.initials: M
authors.lastname: Pajak
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Zheng
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000097:blood; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D003071:Cognition; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000097:blood*
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse