Acta Neuropathologica

, Volume 103, Issue 1, pp 26–35

Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease

  • Jean C. Augustinack
  • Anja Schneider
  • Eva-Maria Mandelkow
  • Bradley T. Hyman
Regular Paper

DOI: 10.1007/s004010100423

Cite this article as:
Augustinack, J.C., Schneider, A., Mandelkow, EM. et al. Acta Neuropathol (2002) 103: 26. doi:10.1007/s004010100423

Abstract

Microtubule associated protein tau is abnormally phosphorylated in Alzheimer's disease (AD) and aggregates as paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). We show here that the pattern of tau phosphorylation correlates with the loss of neuronal integrity. Studies using 11 phosphorylation dependent tau antibodies and a panel of AD cases of varying severity were evaluated in terms of three stages of neurofibrillary tangle development: (1) pre-neurofibrillary tangle, (2) intra-, and (3) extra-neuronal neurofibrillary tangles. The pretangle state, in which neurons display nonfibrillar, punctate regions in the cytoplasm, sound dendrites, somas, and nuclei, was observed especially with phospho-tau antibodies TG3 (pT231), pS262, and pT153. Intraneuronal neurofibrillary tangles are homogenously stained with fibrillar tau structures, which were most prominently stained with pT175/181, 12E8 (pS262/pS356), pS422, pS46, pS214 antibodies. Extracellular NFTs, which contain substantial filamentous tau, are most prominently stained with AT8 (pS199/pS202/pT205), AT100 (pT212/pS214), and PHF-1 (pS396/pS404) antibodies, which also stain intracellular NFT. The sequence of early tau phosphorylation suggests that there are events prior to filament formation that are specific to particular phosphorylated tau epitopes, leading to conformational changes and cytopathological alterations.

Epitope Intraneuronal Extraneuronal Pretangle Neurofibrillary tangle 

Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • Jean C. Augustinack
    • 1
  • Anja Schneider
    • 2
  • Eva-Maria Mandelkow
    • 2
  • Bradley T. Hyman
    • 1
  1. 1.Alzheimer's Unit, Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USAUSA
  2. 2.Max-Plank-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, GermanyGermany
  3. 3.114 16th St., Rm 2009, Alzheimer's Research Unit, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USAUSA

Personalised recommendations