The resulting increase in APP enhances Aβ levels. Importantly, we show that the three genetic isoforms of human ApoE (ApoE2, ApoE3, and ApoE4) exhibit differential potency in stimulating the DLK→MKK7→ERK1/2 MAP-kinase pathway, cFos phosphorylation, APP-gene transcription, and Aβ-synthesis. This differential potency may be relevant for AD since ApoE4 constitutes the most important genetic AD risk factor, whereas ApoE2 protects against AD (Strittmatter et al., 1993; Holtzman et al., 2012; Kanekiyo et al., 2014; Wang and Eckel, 2014). We posit that even though ApoE is only one of several signaling factors that drive APP and Aβ synthesis in neurons, the higher signaling efficacy of ApoE4 than ApoE3 in stimulating APP and Aβ synthesis may cause a cumulative effect over an individual’s lifetime, thus accounting for the increased Aβ-concentrations and AD incidence in individuals expressing ApoE4.
