Neighbored phosphorylation sites as PHF-tau specific markers in Alzheimer's disease.
Neurofibrillary tangles, which represent a major pathological hallmark in Alzheimer's disease (AD), are deposits of the hyperphosphorylated microtubule-associated tau protein (PHF-tau). However, a link between the phosphorylation pattern and the cause or the progress of AD is still missing. The work reported here focused on PHF-tau specific local phosphorylation patterns at Thr212/Ser214 and Thr231/Ser235 using monoclonal antibodies (mAb) generated against correspondingly modified peptides. The binding motifs of the obtained six mAbs were characterized with non-, mono-, and double-phosphorylated peptides as well as terminally shortened sequences. Five mAbs stained neurofibrillary tangles, neuritic plaques, and neuropil threads from autoptic brains of AD cases. Four mAbs recognized PHF-tau without significant cross-reactivity towards normal human tau, bovine tau, and dephosphorylated PHF-tau in ELISA and Western blot analysis. Thus, double phosphorylation is sufficient to distinguish PHF-tau from all other tau versions and there is no need to postulate any PHF-tau specific conformation for this region.
Singer
David
D
Bioanalytics, Center for Biotechnology and Biomedicine (BBZ), Faculty of Chemistry and Mineralogy, University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany.
Lehmann
Jörg
J
Hanisch
Katja
K
Härtig
Wolfgang
W
Hoffmann
Ralf
R
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015415:Biomarkers; D002417:Cattle; D000939:Epitopes / Q000276:immunology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
D015415:Biomarkers; D000939:Epitopes; D016875:tau Proteins; D010769:Phosphothreonine; D010768:Phosphoserine