PKA phosphorylations on tau: developmental studies in the mouse.

PKA phosphorylations of tau may be an early event in the development of neurofibrillary pathology in Alzheimer's disease. Serines 214 and 409 of tau are highly phosphorylated in PHF-tau, but are not phosphorylated to any significant extent in normal adult human brain; both of these sites are phosphorylated in human fetal tissue. To further study this phenomenon, a developmental characterization of these phosphorylation sites relative to PKA, cAMP-dependent response binding element (CREB) and phosphorylated CREB was performed using samples from mouse brain. Immunoblot analysis using antibodies specific for phospho-serine 214 (CP-3) and phospho-serine 409 (PG-5) revealed a marked decrease in phosphorylation occurring at each of these sites between postnatal day 11 (P11) and P20. Immunoblots with TG-5, a pan-tau antibody, revealed uniform expression of tau during postnatal development, as well as a switch in isoform composition that is evident between P7 and P11. This switch in isoform composition just precedes the change in the extent of phosphorylation at serines 214 and 409, and occurs at a time when PKA phosphorylation of CREB is increasing.