Theabnormal phosphorylation oftauprotein atSer-202 in Alzheimer disease recapitulates phosphorylation during development (fetal tau/adult tau/paired helical fIlament/neuropathology)

ABSTRACT Tauis aneuronal phosphoprotein whoseex-pression is developmentally regulated. Asingle tau isoform isexpressedin fetal humanbrainbutsix isoformsareexpressedin adult brain, with the fetal isoform corresponding to theshortest ofthe adult isoforms. Phosphorylation oftau is alsodevelopmentally regulated, as fetal tau is phosphorylated atmoresites than adult tau. In Alzheimerdisease, the six adulttauisoformsbecomeabnormallyphosphorylatedandformthepaired helical filament, the major fibrous component of thecharacteristic neurofibrillary lesions. Weshowhere that Ser-202(in thenumberingofthelongesthumanbraintau isoform) is aphosphorylationsite thatdistinguishesfetalfromadulttauandweidentify it asoneoftheabnormal phosphorylation sitesin Alzheimerdisease. TheabnormalphosphorylationoftauatSer-202 in Alzheimer disease thus recapitulates normal phos-phorylation during development. Microtubule-associated protein tau promotes the assembly and stabilization of neuronal microtubules (for review,