In order to examine the biological functions of ApoE in brain and to explore the contribution of different ApoE isoforms to AD pathogenesis, we here have studied human neurons that were cultured in complete isolation from glial cells and in the absence of serum. This approach enabled us to monitor neuronal responses to different ApoE isoforms in the absence of confounding glial signals, such as endogenous ApoE that is abundantly secreted by cultured glia. Our results reveal that ApoE activates a non-canonical MAP-kinase signaling pathway by binding to cell-surface ApoE-receptors. This pathway consists of DLK as MAP-kinase kinase kinase that phosphorylates MKK7 as MAP-kinase kinase, which in turn phosphorylates ERK1/2 as MAP-kinases (Fig. 7D). Activated ERK1/2 then phosphorylates cFos, a subunit of AP-1 transcription factors; cFos phosphorylation stimulates AP-1-dependent APP gene transcription via an AP-1-binding site in the APP-gene promoter. 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
