Finally, to further probe the role of cFos in ApoE-stimulated APP transcription, we tested the effects of dominant-negative cFos (DN-cFos) overexpressed in human neurons (Olive et al., 1997). DN-cFos did not alter baseline APP mRNA and protein levels, but completely blocked increases in these levels induced by ApoE2, ApoE3, or ApoE4 (Fig. 5G, 5H). Thus, ApoE activates a DLK-dependent MAP-kinase signaling pathway that induces cFos phosphorylation, which stimulates AP-1 and enhances APP synthesis via a direct effect on the APP-gene promoter.
