Secreted beta-APP stimulates MAP kinase and phosphorylation of tau in neurons.
We have previously demonstrated that the secreted form of the beta-amyloid precursor protein (beta-APP) activates mitogen-activated protein (MAP) kinases in PC-12 pheochromocytoma cells. beta-APP as well as other treatments that activate MAP kinase also enhance phosphorylation of the microtubule-associated protein tau in these cells. In this study, we extended this analysis to neurons. Using dissociated cultures of cortical neurons, we found that exposure to beta-APP activated MAP kinase 4 and 7 days but not 1 day after plating. Phosphorylation of tau in neurons was measured by immunoreactivity with the AT8 antibody, which recognizes a phosphorylated epitope present in tau from paired helical filaments. We found that activation of MAP kinase in neurons was associated with increased amounts of AT8-reactive tau. These results support a role for MAP kinase in transducing the biological effects of secreted beta-APP on neurons and suggest possible mechanisms by which beta-APP might be involved in the pathogenesis of Alzheimer's disease.
Greenberg
S M
SM
Department of Neurology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
Kosik
K S
KS
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D016875:tau Proteins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases