Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer's disease and Down syndrome

Neuropathol Appl Neurobiol. 2014 Feb;40(2):121-35. doi: 10.1111/nan.12084.


Aims: Phosphorylation, conformational changes and cleavage of tau protein have been widely suggested to contribute to abnormal tau processing in the pathogenesis of Alzheimer's disease, as well as in other tauopathies. Consistently, many phosphorylated sites, such as Ser(199-202) -Thr(205) and Ser(396-404) , have been associated with this pathological processing. The present study examined the chronological appearance of phosphorylation during the neurofibrillary tangle (NFT) evolution in Alzheimer disease (AD) and Down syndrome.

Methods: Immunohistochemistry for modified tau [phosphorylated at Ser(199-202) -Thr(205) (AT8) and Ser(396-404) (PHF-1) or truncated at D(421) (TauC3) and E(391) (MN423)] was performed on paraffin-embedded human brain sections. Double immunofluorescence for phosphorylated and truncated tau was used to detect intensity and distribution of tau immunoreactivity, and provided detailed characterization of NFT pathology.

Results: Phosphorylation at sites Ser(396-404) was significantly increased when compared with phosphorylations at sites Ser(199-202) -Thr(205) . Around 50% of the total structures containing phosphorylation at sites Ser(396-404) were found as early phospho-tau aggregates with a well-preserved neuronal soma. Phosphorylation of tau protein at sites Ser(396) coexists with early and late truncation events. Tau abnormal processing in Down syndrome consistently showed similar alterations as observed in AD.

Conclusion: Phosphorylation of tau protein at the carboxyl terminus may be among the earliest tau events, and it occurs prior to the apparition of the classical fibrillar structure. Finally, these data validate PHF-1 as an efficient marker for AD cytopathology following the progression of tau aggregation into NFT.

Keywords: Alzheimer disease; Down syndrome; cleavage; early event; phosphorylation; tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Brain / metabolism*
  • Brain / pathology
  • Disease Progression
  • Down Syndrome / metabolism*
  • Down Syndrome / pathology
  • Humans
  • Middle Aged
  • Neurofibrillary Tangles / pathology
  • Phosphorylation
  • tau Proteins / metabolism*


  • tau Proteins