Phosphorylation of tau protein at sites Ser396–404 is one of the earliest events in Alzheimer's disease and Down syndrome
Article first published online: 21 JAN 2014
© 2013 British Neuropathological Society
Neuropathology and Applied Neurobiology
Volume 40, Issue 2, pages 121–135, February 2014
How to Cite
Mondragón-Rodríguez, S., Perry, G., Luna-Muñoz, J., Acevedo-Aquino, M. C. and Williams, S. (2014), Phosphorylation of tau protein at sites Ser396–404 is one of the earliest events in Alzheimer's disease and Down syndrome. Neuropathology and Applied Neurobiology, 40: 121–135. doi: 10.1111/nan.12084
- Issue published online: 21 JAN 2014
- Article first published online: 21 JAN 2014
- Accepted manuscript online: 23 AUG 2013 03:43AM EST
- Manuscript Accepted: 23 AUG 2013
- Manuscript Revised: 21 AUG 2013
- Manuscript Received: 2 NOV 2012
- National Center for Research Resources. Grant Number: 5 G12RR013646-12
- National Institute on Minority Health and Health Disparities. Grant Number: G12MD007591
- Research Centers in Minority Institutions (RCMI)
- FRSQ, Canada
- Alzheimer disease;
- Down syndrome;
- early event;
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 Ser199–202–Thr205 and Ser396–404, 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.
Immunohistochemistry for modified tau [phosphorylated at Ser199–202–Thr205 (AT8) and Ser396–404 (PHF-1) or truncated at D421 (TauC3) and E391 (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.
Phosphorylation at sites Ser396–404 was significantly increased when compared with phosphorylations at sites Ser199–202–Thr205. Around 50% of the total structures containing phosphorylation at sites Ser396–404 were found as early phospho-tau aggregates with a well-preserved neuronal soma. Phosphorylation of tau protein at sites Ser396 coexists with early and late truncation events. Tau abnormal processing in Down syndrome consistently showed similar alterations as observed in AD.
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.