cAMP-dependent protein kinase phosphorylations on tau in Alzheimer's disease

To elucidate the role cAMP-dependent protein kinase (PKA) phosphorylations on tau play in Alzheimer's disease, we have generated highly specific monoc lonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphor ylations of ser214 and ser409 in tau respectively. The present study demons trates by immunohistochemical analysis, CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer's disease, but not in normal brain tissue and demonstrates that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau. Studies using heat-stable prep arations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demons trates that the beta catalytic subunit of PKA (C beta), the beta II regulat ory subunit of PKA (RII beta), and the 79 kDa A-kinase-anchoring-protein (A KAP79), are tightly associated with the neurofibrillary pathology, position ing cAMP-dependent protein kinase to participate directly in the pathologic al hyperphosphorylation of tau seen in Alzheimer's disease.