A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer's disease brain

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Ebru Ercan-Herbst - (Author)
  • Jens Ehrig - , Core Facility Molecular Imaging and Manipulation (Author)
  • David C. Schöndorf - (Author)
  • Annika Behrendt - (Author)
  • Bernd Klaus - (Author)
  • Borja Gomez Ramos - (Author)
  • Nuria Prat Oriol - (Author)
  • Christian Weber - (Author)
  • Dagmar E. Ehrnhoefer - (Author)

Abstract

Tau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer's disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0-I, II or III-IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III-IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

Details

Original languageEnglish
Article number192
JournalActa neuropathologica communications
Volume7
Issue number1
Publication statusPublished - 3 Dec 2019
Peer-reviewedYes

External IDs

PubMed 31796124

Keywords

Sustainable Development Goals

Keywords

  • Alzheimer's disease, Posttranslational modifications, Tau, Tau oligomerization

Library keywords