In blood, apolipoprotein E (ApoE) is a component of circulating lipoproteins and mediates the clearance of these lipoproteins from blood by binding to ApoE receptors. Humans express three genetic ApoE variants, ApoE2, ApoE3, and ApoE4, which exhibit distinct ApoE receptor-binding properties and differentially affect Alzheimer's disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to AD. In brain, ApoE-containing lipoproteins are secreted by activated astrocytes and microglia, but their functions and role in AD pathogenesis are largely unknown. Ample evidence suggests that ApoE4 induces microglial dysregulation and impedes A clearance in AD, but the direct neuronal effects of ApoE variants are poorly studied. Extending previous studies, we here demonstrate that the three ApoE variants differentially activate multiple neuronal signaling pathways and regulate synaptogenesis. Specifically, using human neurons (male embryonic stem cell-derived) cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates signal transduction cascades. Among others, such stimulation enhances APP synthesis and synapse formation with an ApoE4ϾApoE3ϾApoE2 potency rank order, paralleling the relative risk for AD conferred by these ApoE variants. Unlike the previously described induction of APP transcription, however, ApoE-induced synaptogenesis involves CREB activation rather than cFos activation. We thus propose that in brain, ApoE acts as a glia-secreted signal that activates neuronal signaling pathways. The parallel potency rank order of ApoE4ϾApoE3ϾApoE2 in AD risk and neuronal signaling suggests that ApoE4 may in an apparent paradox promote AD pathogenesis by causing a chronic increase in signaling, possibly via enhancing APP expression.
At tripartite synapses, astrocytes surround synaptic contacts, but how astrocytes contribute to the assembly and function of synapses remains unclear. Here we show that neurexin-1α, a presynaptic adhesion molecule that controls synapse properties, is also abundantly expressed by astrocytes. Strikingly, astrocytic neurexin-1α, but not neuronal neurexin-1α, is highly modified by heparan sulfate. Moreover, astrocytic neurexin-1α is uniquely alternatively spliced and invariably contains an insert in splice-site #4, thereby restricting the range of ligands to which it binds. Deletion of neurexin-1 from astrocytes or neurons does not alter synapse numbers or synapse ultrastructure, but differentially impairs synapse function. At hippocampal Schaffer-collateral synapses, neuronal neurexin-1 is essential for normal NMDA-receptor-mediated synaptic responses, whereas astrocytic neurexin-1 is required for normal AMPA-receptor-mediated synaptic responses and for long-term potentiation of these responses. Thus, astrocytes directly shape synapse properties via a neurexin-1-dependent mechanism that involves a specific molecular program distinct from that of neuronal neurexin-1.
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 Ab 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. 239 words 3
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