ABSTRACT
Alzheimer’s disease (AD) is characterized by the presence of two aberrant structures, senile plaques, composed of amyloid-β protein (Aβ), and neurofibrillary tangles (NFT), composed of paired helical filaments (PHF). Isolated PHF are characterized by three different methods: amino acid analysis, gel electrophoresis and immunoelectron microscopy. These have indicated the presence of a high proportion (3-4%) of phosphoserine and threonine residues in PHF protein; an abnormal electrophoretic mobility of tau protein present in PHF, which can be reversed by phosphatase treatment; and the binding of antibodies recognizing phosphoepitopes of tau protein in PHF. These three features support the pioneer observation that tau protein in PHF is in a hyperphosphorylated state.1,2
Different kinases have been involved in tau phosphorylation3 and different motifs for those kinases are present in the tau molecule. The motif S/TXXXS/T, which is the sequence modified by GSK3 kinase, is repeated 22 times in
the tau molecule, and several of these sites have been confirmed in vivo.4,5
Furthermore, a transgenic mouse overexpressing GSK3 has been generated, resembling some pathological tau features observed in AD,6
including behavior deficits, as determined by the Morris water maze test.7 However, in this transgenic mouse the formation of PHF-like structures was not observed, although the presence of aggregated phosphorylated tau was not excluded.6 This observation suggests that tau phosphorylation might be unrelated to tau filament formation; or that it could be necessary, but not sufficient, for that assembly.
