Anti-apoptotic wild-type Alzheimer amyloid precursor protein signaling involves the p38 mitogen-activated protein kinase/MEF2 pathway.
Alzheimer amyloid precursor protein (APP) effectively protects against apoptosis in neuronal cells under stress, but the mechanisms of this anti-apoptotic effect remain largely unknown. Transcription factors act as critical molecular switches in promoting neuronal survival. The myocyte enhancer factor-2 (MEF2) is a transcription factor, and is known to be necessary for neurogenesis and activity-dependent neuronal survival. This study examined the possible role of MEF2 in the anti-apoptotic signaling pathways activated by APP. We report that expression of wild-type human APP (hAPPwt) but not familial Alzheimer's disease mutant APP (FAD-hAPPmut) in APP-deficient rat B103 cells led to a significant increase in the level of phosphorylated MEF2. This differential phosphorylation was dependent on enhanced activation of p38 mitogen-activated protein kinase (p38 MAPK). Also, expression of hAPPwt mediated an increase in MEF2 DNA binding affinity that correlated with p38 MAPK-dependent trans-activation of a MEF2-responsive reporter gene. Furthermore, over-expression of dominant negative MEF2 in hAPPwt-expressing cells enhanced staurosporine-induced apoptosis, in contrast MEF2wt enhanced the capacity of hAPPwt to confer resistance to apoptosis. Thus, MEF2 plays a critical role in APP-mediated signaling pathways that inhibit neuronal apoptosis. A model of anti-apoptotic APP signaling is proposed where APP mediates p38 MAPK-dependent phosphorylation and activation of MEF2. Once activated MEF2 regulates neuronal survival by stimulation of MEF2-dependent gene transcriptions. Alteration of this function by mutations in APP and aberrant APP processing could contribute to neuronal degeneration seen in AD.
Burton
Teralee R
TR
The Dr. John Foerster Center for Health Research on Aging, St. Boniface General Hospital Research Center, 351 Taché Avenue, Winnipeg, MB R2H 2A6, Canada.
Dibrov
Alex
A
Kashour
Tarek
T
Amara
Francis M
FM
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D064326:MEF2 Transcription Factors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D018006:Myogenic Regulatory Factors; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases