ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion

Huang, Yu-Wen Alvin; Zhou, Bo; Wernig, Marius; Südhof, Thomas C.

doi:10.1016/j.cell.2016.12.044

Cited by 528Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion

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Huang, Yu-Wen Alvin, Zhou, Bo, Wernig, Marius, Südhof, Thomas C.·2017·Cell

DOI 10.1016/j.cell.2016.12.044PMC PMC5310835

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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 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.

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These APOE4 pathway effects are consistent with reported roles of APOE4 in inflammation, synaptic impairment, MAPK1 signaling and downstream APP transcription, and early endosomes.
“All these effects are consistent with reported roles of APOE4 in inflammation, synaptic impairment, MAPK1 signaling and downstream APP transcription, and early endosomes7,18.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [18]
The Discussion (page unavailable) reports that ApoE4 is more potent than other ApoE isoforms in activating an ERK1/2 MAP-kinase pathway that stimulates APP transcription. The passages do not establish the other attributed roles—inflammation, synaptic impairment, or early endosomes—and the paper describes ERK1/2 rather than naming MAPK1 specifically. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Differences in APOE isoform-specific receptor binding affinity and lipid interactions affect neuroinflammation, tau pathology, and amyloid plaque dynamics.
“Studies indicate that APOE binding is integral to some of these processes [16–20] with differences in APOE isoform-specific receptor binding affinity and lipid interactions affecting neuroinflammation, tau pathology, and amyloid plaque dynamics [21–24].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [22]
The Results report that ApoE2, ApoE3, and ApoE4 differ in their ability to stimulate Aβ synthesis in human neurons; the Discussion links that effect to ApoE-receptor signaling. The Introduction also notes an association between ApoE4 and Aβ accumulation. The paper does not establish that differences in receptor-binding affinity or lipid interactions cause these effects, and it does not address effects on neuroinflammation or tau pathology. (LLM, conf=0.85)
Experimental — accuracy not yet measured
APOE and APOE3Ch influence both Aβ and tau pathology, either directly or through downstream effects such as neuroinflammation.
“Collectively, these recent findings underscore the influence of APOE and APOE3Ch on both Aβ and tau pathology, either directly or through downstream effects such as neuroinflammation.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [22]
The Abstract and Discussion report that ApoE2, ApoE3, and ApoE4 stimulate APP transcription and Aβ production in neurons. The cited paper does not establish effects of APOE3Ch on Aβ or effects of either APOE or APOE3Ch on tau pathology or neuroinflammation. Page numbers are unavailable in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Raised APOE leads to an increase in APP transcript expression in preclinical models via an effect on the transcription factor AP1.
“A previous report has indicated that raised APOE leads to an increase in APP transcript expression in preclinical models via an effect on the transcription factor AP1 [29].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [29]
APOE isoforms can differentially influence the transcription of Aβ precursor protein and the generation of Aβ; these factors are most increased by APOE4, followed by APOE3, then APOE2.
“Besides promoting Aβ aggregation and impairing its clearance, APOE isoforms can also differentially influence the transcription of Aβ precursor protein and the generation of Aβ; these factors are most increased by APOE4, followed by APOE3, then APOE2 (ref. 121).”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [121]

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Authors: Huang, Y.-W. A., Zhou, B., Wernig, M., & Südhof, T. C.
Affiliations: Howard Hughes Medical Institute (US)
Stanford Medicine (US)
Corresponding author: Südhof, Thomas C.
ORCID: Huang, Yu-Wen Alvin
Zhou, Bo
Wernig, Marius
Südhof, Thomas C.
Venue: Cell
Publisher: Elsevier BV
Published: 2017-01
Volume: 168
Issue: 3
Pages: 427-441.e21
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2016.12.044
PMC: PMC5310835
OpenAlex: W2576070094
Cited by: 528
References: 49
Citations by year: 2026: 39 · 2025: 57 · 2024: 61 · 2023: 64 · 2022: 53 · 2021: 59 · 2020: 69 · 2019: 58 · 2018: 47 · 2017: 21
FWCI: 39.85
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 390 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: NIH (AG04813101)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: apolipoprotein E isoforms, APOE ε4, APOE2, APOE3, amyloid-beta secretion, Alzheimer's disease, dual leucine zipper kinase, MKK7, ERK1/2 MAP kinase, AP-1 transcription factor, neuronal transduction, MAP kinase cascade
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Fibroblasts, Humans, Neurons, Amyloid beta-Protein Precursor, Protein Isoforms, MAP Kinase Signaling System, Mice, Embryonic Stem Cells

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ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion

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