ApoE2, ApoE3 and ApoE4 Differentially Impact Multiple Signaling Pathways Regulating Synaptogenesis

Apolipoprotein E (ApoE) mediates clearance of circulating lipoproteins from blood by binding to ApoE receptors. Humans express three ApoE genetic variants, ApoE2, ApoE3, and ApoE4, that exhibit distinct ApoE receptor binding properties. However, ApoE is also abundantly produced in brain by activated astrocytes and microglia. Here, the three variants differentially affect Alzheimer's disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to AD. A role for ApoE4 in driving microglial dysregulation in AD and impeding A{beta} clearance is well documented, but the possible direct effects of ApoE4 on neurons are poorly understood. Extending previous studies, we here demonstrate that ApoE variants differentially activate multiple neuronal signaling pathways by binding to ApoE receptors on human neurons. Specifically, using human neurons cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates multiple signal transduction cascades. These cascades among others enhance synapse formation with an ApoE4>ApoE3>ApoE2 potency rank order, paralleling the relative risk for AD conferred by these three variants. ApoE-induced synaptogenesis required MAP-kinase activation similar to induction of APP transcription, but involved CREB activation instead of cFos activation. We thus propose that in brain, ApoE acts as a paracrine signal that is secreted by astrocytes and microglia in response to neuroinflammation, and broadly activates neuronal signaling pathways in what may represent a protective response, with the differential potency of ApoE variants causing distinct levels of chronic signaling that may contribute to AD pathogenesis.