Our results raise important new questions, both about the mechanism and the conceptual implications of the signaling pathway that we describe. For example, which ApoE receptor mediates activation of DLK, and how is the ApoE signal transduced? ApoE receptors bind to adaptor proteins, such as Disabled-1 and X11/Mints, thereby mediating signal transduction (Gotthardt et al., 2000). Clearly, a similar pathway could operate in DLK activation. Another mechanistic question regards the differential efficacy of ApoE2, ApoE3, and ApoE4 in activating ApoE receptors – is this effect due to different binding affinities, or to different agonist potencies? This important issue can be addressed once the relevant ApoE receptor for signaling in neurons has been identified (Fig. 7D). Among broader questions, those regarding the general function of the ApoE-stimulated MAP-kinase signaling pathway may be paramount – what is its overall role, and which other biological processes are regulated by this pathway? Moreover, what is the biological function of APP, an issue that has been debated for decades, and why is expression of APP but not of APLP1 or APLP2 increased by ApoE signaling?
