Cell
Volume 168, Issue 3, 26 January 2017, Pages 427-441.e21
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Article
ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion

https://doi.org/10.1016/j.cell.2016.12.044Get rights and content
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Highlights

  • Human ApoE robustly stimulates APP transcription and Aβ production in human neurons

  • ApoE4 is more potent and ApoE2 less potent than ApoE3 in stimulating Aβ production

  • ApoE activates a non-canonical MAP kinase pathway involving DLK, MKK7, and ERK1/2

  • ApoE-activated MAP kinases phosphorylate cFos to induce APP and Aβ production

Summary

Human apolipoprotein E (ApoE) apolipoprotein is primarily expressed in three isoforms (ApoE2, ApoE3, and ApoE4) that differ only by two residues. ApoE4 constitutes the most important genetic risk factor for Alzheimer’s disease (AD), ApoE3 is neutral, and ApoE2 is protective. How ApoE isoforms influence AD pathogenesis, however, remains unclear. Using ES-cell-derived human neurons, we show that ApoE secreted by glia stimulates neuronal Aβ production with an ApoE4 > ApoE3 > ApoE2 potency rank order. We demonstrate that ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases. Activated ERK1/2 induces cFos phosphorylation, stimulating the transcription factor AP-1, which in turn enhances transcription of amyloid-β precursor protein (APP) and thereby increases amyloid-β levels. This molecular mechanism also regulates APP transcription in mice in vivo. Our data describe a novel signal transduction pathway in neurons whereby ApoE activates a non-canonical MAP kinase cascade that enhances APP transcription and amyloid-β synthesis.

Keywords

apolipoprotein E
ApoE
Alzheimer’s disease
MAP kinase signaling
amyloid precursor protein
APP
beta amyloid
cFos
CRISPR
CRISPRi
dual leucine-zipper kinase
DLK
transcription

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