Neurofibrillary tangles, one of the major pathological hallmarks of Al
zheimer-diseased brains, consist primarily of aggregated paired helica
l filaments (PHFs) of hyperphosphorylated tau protein. tau from normal
brain and especially from foetal brain is also phosphorylated on some
of the sites phosphorylated in PHFs, mainly at serines or threonines
followed by prolines. A number of protein kinases can phosphorylate ta
u in vitro; those that require or accept prolines include GSK3 and mem
bers of the mitogen-activated protein (MAP) kinase family, ERK1, ERK2,
and SAP kinase-beta/JNK. In this report, we show that another member
of the MAP kinase family, the stress-activated kinase p38/RK, can phos
phorylate tau in vitro. Western blots with phosphorylation-sensitive a
ntibodies showed that p38, like ERK2 and SAP kinase-beta/JNK, phosphor
ylated tau at sites found phosphorylated physiologically (Thr(181), Se
r(202), Thr(205), and Ser(396)) and also at Ser(422), which is phospho
rylated in neurofibrillary tangles but not in normal adult or foetal b
rain. These findings support the possibility that cellular stress migh
t contribute to tau hyperphosphorylation during the formation of PHFs,
and hence, to the development of tau pathology.