Collectively, these observations suggest that ApoE may normally function in brain as a lipid-transport and/or signaling molecule, and that ApoE4 may predispose to AD because it affects the production, clearance, and/or toxicity of Aβ (Holtzman et al., 2012). However, these observations are based on experiments that analyzed glial cells and neurons together – either in vitro or in vivo – and focused on rodents. Here, we took a different approach, and examined the effects of recombinant ApoE2, ApoE3, and ApoE4 on human neurons that were cultured without glia to exclude the confounding influence of secreted factors produced by glia, including glial ApoE. We show that ApoE is indeed a signaling molecule, demonstrate that ApoE activates an unusual MAP-kinase signaling cascade, document that this cascade stimulates cFos phosphorylation and APP-gene transcription, and show that this stimulation leads to increased APP and Aβ synthesis. Most importantly, we show that the intrinsic efficacy in activating this pathway differs dramatically between ApoE2, ApoE3, and ApoE4, mirroring their relative effect on AD pathogenesis. Thus, our data uncover an ApoE-dependent signaling pathway that may perform a general role in brain as well as contribute a significant component to AD pathogenesis.
