Physiologic levels of beta-amyloid activate phosphatidylinositol 3-kinase with the involvement of tyrosine phosphorylation.
The beta-amyloid protein (A beta) peptide plays an important role in Alzheimer's disease, but the potential actions of physiologic levels of A beta (225-625 pM) have not been explored. We recently showed that picomolar doses of A beta can stimulate tyrosine phosphorylation of neuronal cells and now show that leads to the activation of the lipid kinase phosphatidylinositol 3-kinase (PI3 kinase). Three independent lines of evidence support the hypothesis that A beta is activating PI3 kinase through a tyrosine kinase-mediated mechanism. Immunoblotting studies show that A beta induces tyrosine phosphorylation of p85 as well as association of the p85 subunit of PI3 kinase with tyrosine-phosphorylated proteins. Studies of membrane proteins show that A beta induces a translocation of p85 to membrane-bound glycoproteins, which are likely to be receptors. Finally, direct studies of PI3 kinase activity in both anti-phosphotyrosine immunocomplexes and wheat germ agglutinin precipitates show that A beta increases formation of the product of PI3 kinase. Wortmannin, a selective inhibitor of PI3 kinase, blocks this A beta-stimulated PI3 kinase activity. Thus, physiologic levels of A beta stimulate tyrosine phosphorylation and PI3 kinase activity.
Luo
Y
Y
Section on Geriatric Psychiatry, NIMH, Bethesda, Maryland 20892-1264, USA.
Sunderland
T
T
Wolozin
B
B
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured / Q000201:enzymology; D002540:Cerebral Cortex / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008970:Molecular Weight; D009474:Neurons / Q000201:enzymology; D016716:PC12 Cells / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)