ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Abeta Secretion.

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Huang YA, Zhou B, Wernig M, Sudhof TC

ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Abeta Secretion.

Cell. 2017 Jan 26;168(3):427-441.e21. doi: 10.1016/j.cell.2016.12.044. Epub 2017 Jan 19.

PubMed ID
28111074 [ View in PubMed
]
Abstract

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 Abeta 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-beta precursor protein (APP) and thereby increases amyloid-beta 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-beta synthesis.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Dual specificity mitogen-activated protein kinase kinase 7O14733Details