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Phosphorylation of tau protein at sites Ser 396–404 is one of the earliest events in A lzheimer's disease and D own syndrome
Author(s) -
MondragónRodríguez S.,
Perry G.,
LunaMuñoz J.,
AcevedoAquino M. C.,
Williams S.
Publication year - 2014
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12084
Subject(s) - phosphorylation , tau protein , neurofibrillary tangle , alzheimer's disease , pathogenesis , immunohistochemistry , microbiology and biotechnology , pathology , biology , chemistry , senile plaques , medicine , disease
Aims Phosphorylation, conformational changes and cleavage of tau protein have been widely suggested to contribute to abnormal tau processing in the pathogenesis of A lzheimer'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 A lzheimer disease ( AD ) and D own syndrome. Methods Immunohistochemistry for modified tau [phosphorylated at Ser 199–202 – Thr 205 ( AT 8) and Ser 396–404 ( PHF ‐1) or truncated at D 421 ( TauC 3) and E 391 ( MN 423)] 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 D own 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 .