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 monoclonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphorylations of ser214 and ser409 in tau respectively. The present study demonstrates 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 preparations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demonstrates that the beta catalytic subunit of PKA (Cbeta), the beta II regulatory subunit of PKA (RIIbeta), and the 79 kDa A-kinase-anchoring-protein (AKAP79), are tightly associated with the neurofibrillary pathology, positioning cAMP-dependent protein kinase to participate directly in the pathological hyperphosphorylation of tau seen in Alzheimer's disease.
Jicha
G A
GA
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Weaver
C
C
Lane
E
E
Vianna
C
C
Kress
Y
Y
Rockwood
J
J
Davies
P
P
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D001921:Brain / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005333:Fetus; D038362:Glycogen Synthase Kinase 3; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000473:pathology; D009928:Organ Specificity; D010446:Peptide Fragments / Q000737:chemistry; D010748:Phosphopeptides / Q000737:chemistry; D010766:Phosphorylation; D051381:Rats; D012016:Reference Values; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D010748:Phosphopeptides; D016875:tau Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3