Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer’s disease

Research output: Contribution to journalArticle

Abstract

Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer’s disease (AD). Most of tau in CSF is present as fragments. We immunoprecipitated tau from CSF and identified several endogenous peptides ending at amino acid (aa) 123 or 224 using high-resolution mass spectrometry. We raised neo-epitope-specific antibodies against tau fragments specifically ending at aa 123 and 224, respectively. With these antibodies, we performed immunohistochemistry on brain tissue and designed immunoassays measuring N-123, N-224, and x-224 tau. Immunoassays were applied to soluble brain fractions from pathologically confirmed subjects (81 AD patients, 33 controls), CSF from three cross-sectional and two longitudinal cohorts (a total of 133 AD, 38 MCI, 20 MCI-AD, 31 PSP, 15 CBS patients, and 91 controls), and neuronally- and peripherally-derived extracellular vesicles (NDEVs and PDEVs, respectively) in serum from four AD patients and four controls. Anti-tau 224 antibody stained neurofibrillary tangles and neuropil threads, while anti-tau 123 only showed weak cytoplasmic staining in AD. N-224 tau was lower in the AD soluble brain fraction compared to controls, while N-123 tau showed similar levels. N-224 tau was higher in AD compared to controls in all CSF cohorts (p < 0.001), but not N-123 tau. Decrease in cognitive performance and conversion from MCI to AD were associated with increased baseline CSF levels of N-224 tau (p < 0.0001). N-224 tau concentrations in PSP and CBS were significantly lower than in AD (p < 0.0001) and did not correlate to t-tau and p-tau. In a longitudinal cohort, CSF N-224 tau levels were stable over 6 months, with no significant effect of treatment with AChE inhibitors. N-224 tau was present in NDEVs, while N-123 tau showed comparable concentrations in both vesicle types. We suggest that N-123 tau is produced both in CNS and PNS and represents a general marker of tau metabolism, while N-224 tau is neuron-specific, present in the tangles, secreted in CSF, and upregulated in AD, suggesting a link between tau cleavage and propagation, tangle pathology, and cognitive decline.

Details

Authors
  • Claudia Cicognola
  • Gunnar Brinkmalm
  • Jessica Wahlgren
  • Erik Portelius
  • Johan Gobom
  • Nicholas C. Cullen
  • Oskar Hansson
  • Lucilla Parnetti
  • Radu Constantinescu
  • Kristin Wildsmith
  • Hsu Hsin Chen
  • Thomas G. Beach
  • Tammaryn Lashley
  • Henrik Zetterberg
  • Kaj Blennow
  • Kina Höglund
Organisations
External organisations
  • Sahlgrenska University Hospital
  • University of Pennsylvania
  • Skåne University Hospital
  • University of Perugia
  • Genentech, Inc
  • Banner Sun Health Research Institute
  • University College London
  • University of Gothenburg
  • Karolinska Institutet
  • Ospedale Santa Maria della Misericordia
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology

Keywords

  • Alzheimer’s disease, Cerebrospinal fluid, Immunohistochemistry, Mass spectrometry, Tau fragments
Original languageEnglish
Pages (from-to)279-296
JournalActa Neuropathologica
Volume137
Issue number2
Early online date2018 Dec 13
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes