Detection of phosphorylated Ser262 in fetal tau, adult tau, and paired helical filament tau.
Paired helical filaments (PHFs) are the major structural elements of Alzheimer's disease neurofibrillary lesions, and these filaments are formed from hyperphosphorylated brain tau known as PHF-tau. Recent studies showed that many previously identified phosphorylated residues in PHF-tau also are phosphate acceptor sites in fetal and rapidly processed adult brain tau. However, Ser262 has been suggested to be uniquely phosphorylated in PHF-tau and a key regulator of the binding of tau to microtubules. For these reasons, we generated a monoclonal antibody (12E8) specific for phosphorylated Ser262 and showed that 12E8 binds to PHF-tau, rat and human fetal brain tau, as well as to rapidly processed adult rat and biopsy-derived human brain tau. Further, phosphorylation Ser262 was developmentally regulated, and endogenous brain phosphatases rapidly dephosphorylated Ser262 in biopsy-derived brain tau isolates. Finally, the phosphorylation of Ser262 did not eliminate the binding of tau to microtubules. Thus, we speculate that the binding of tau to microtubules is regulated by phosphorylation at multiple sites and that the generation of PHF-tau in Alzheimer's disease results from the reduced efficiency of phosphatases leading to the incremental accumulation of hyperphosphorylated tau.
Seubert
P
P
Athena Neurosciences, Incorporated, South San Francisco, California 94080, USA.
Mawal-Dewan
M
M
Barbour
R
R
Jakes
R
R
Goedert
M
M
Johnson
G V
GV
Litersky
J M
JM
Schenk
D
D
Lieberburg
I
I
Trojanowski
J Q
JQ
D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001706:Biopsy; D005260:Female; D005333:Fetus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D012694:Serine