General Information:

Id: 7,250 (click here to show other Interactions for entry)
Diseases: Alzheimer disease - [OMIM]
Homo sapiens
HEK293 cells; ES-cell-derived human neurons
article
Reference: Huang YA et al.(2017) ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Abeta Secretion Cell 168: 427-441.e21 [PMID: 28111074]

Interaction Information:

Comment ApoE increases APP expression 3-4-fold with an ApoE4>ApoE3>ApoE2 potency rank order by activating the DLK-> MKK7 -> ERK1/2 MAP-kinase pathway.
Formal Description
Interaction-ID: 71302

gene/protein mutant

APOE (isoform E4)

increases_expression of

gene/protein

APP

in human neurons; compared to ApoE3 and ApoE2
Drugbank entries Show/Hide entries for APP
Comment ApoE2, ApoE3, and ApoE4 differentially stimulate Abeta40 and Abeta42 secretion by human neurons cultured on MEFs (murine embryonic fibroblasts) with an ApoE4 > ApoE3 > ApoE2 potency rank order.
Formal Description
Interaction-ID: 71312

gene/protein mutant

APOE (isoform E4)

increases_activity of

process

Abeta (42) secretion

in human neurons cultured on MEFs ; compared to ApoE3 and ApoE2
Comment ApoE2, ApoE3, and ApoE4 differentially stimulate Abeta40 and Abeta42 secretion by human neurons cultured on MEFs (murine embryonic fibroblasts) with an ApoE4 > ApoE3 > ApoE2 potency rank order.
Formal Description
Interaction-ID: 71315

gene/protein mutant

APOE (isoform E4)

increases_activity of

process

Abeta (40) secretion

in human neurons cultured on MEFs ; compared to ApoE3 and ApoE2
Comment The three human ApoE isoforms increased DLK levels with the same differential potency as for the stimulation of Abeta synthesis and ERK1/2 phosphorylation (ApoE4>ApoE3>ApoE2). 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.
Formal Description
Interaction-ID: 71334

gene/protein mutant

APOE (isoform E4)

increases_activity of

gene/protein

MAP3K12

in human neurons; compared to ApoE3 and ApoE2; via binding to ApoE receptors
Comment ApoE4 constitutes the most important genetic risk factor for Alzheimer’s disease (AD), ApoE3 is neutral, and ApoE2 is protective. The higher signaling efficacy of ApoE4 than ApoE3 in stimulating APP and Abeta synthesis may cause a cumulative effect over an individual’s lifetime, thus accounting for the increased Abeta concentrations and AD incidence in individuals expressing ApoE4.
Formal Description
Interaction-ID: 71364

gene/protein mutant

APOE (isoform E4)

increases_activity of

disease

Alzheimer disease

if human neurons are cultured on mouse glia;
Comment All three ApoE isoforms robustly enhanced Abeta-synthesis, but with strikingly different efficacy (ApoE4>ApoE3>ApoE2). This differential efficacy was observed for total Abeta, Abeta40, or Abeta42, and for secreted as well as cellular Abeta, and was unrelated to alpha-or beta-secretase expression.
Formal Description
Interaction-ID: 124911

gene/protein mutant

APOE (isoform E4)

increases_quantity of

gene/protein

Amyloid beta peptide (42)

compared to ApoE3 and ApoeE2; unrelated to alpha-or beta-secretase expression
Comment All three ApoE isoforms robustly enhanced Abeta-synthesis, but with strikingly different efficacy (ApoE4>ApoE3>ApoE2). This differential efficacy was observed for total Abeta, Abeta40, or Abeta42, and for secreted as well as cellular Abeta, and was unrelated to alpha-or beta-secretase expression.
Formal Description
Interaction-ID: 124917

gene/protein mutant

APOE (isoform E4)

increases_quantity of

gene/protein

Amyloid beta peptide (40)

compared to ApoE3 and ApoeE2; unrelated to alpha-or beta-secretase expression