General Information:

Id: 7,250
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 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: 71309

gene/protein mutant

APOE (isoform E3)

increases_expression of

gene/protein

APP

compared to 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 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: 71324

gene/protein mutant

APOE (isoform E3)

increases_activity of

process

Abeta (42) secretion

in human neurons cultured on MEFs ; compared to 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: 71325

gene/protein mutant

APOE (isoform E3)

increases_activity of

process

Abeta (40) secretion

in human neurons cultured on MEFs ; compared to 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 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: 71344

gene/protein mutant

APOE (isoform E3)

increases_activity of

gene/protein

MAP3K12

in human neurons; compared to ApoE2; via binding to ApoE receptors
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: 71345

gene/protein mutant

APOE (isoform E2)

decreases_activity of

gene/protein

MAP3K12

in human neurons; compared to ApoE4 and ApoE3; via binding to ApoE receptors
Comment 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: 71346

gene/protein

MAP3K12

increases_activity of

gene/protein

MAP2K7

in human neurons; if activated via binding to ApoE receptors;
Comment 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: 71347

gene/protein

MAP2K7

increases_activity of

gene/protein

MAPK3

in human neurons
Drugbank entries Show/Hide entries for MAPK3
Comment 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: 71348

gene/protein

MAP2K7

increases_activity of

gene/protein

MAPK1

in human neurons
Drugbank entries Show/Hide entries for MAPK1
Comment 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: 71349

gene/protein

MAPK1

increases_phosphorylation of

gene/protein

FOS

in human neurons; if MAPK1/ERK2 is activated;
Drugbank entries Show/Hide entries for MAPK1 or FOS
Comment 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: 71350

gene/protein

MAPK3

increases_phosphorylation of

gene/protein

FOS

in human neurons; if MAPK3/ERK1 is activated;
Drugbank entries Show/Hide entries for MAPK3 or FOS
Comment 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: 71351

gene/protein

FOS

increases_activity of

gene/protein

JUN

if C-FOS is phosphorylated;
Drugbank entries Show/Hide entries for FOS or JUN
Comment 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: 71353

gene/protein

FOS

increases_expression of

gene/protein

APP

in human neurons; if phosphorylated;
Drugbank entries Show/Hide entries for FOS or APP
Comment 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: 71355

gene/protein

APP

increases_quantity of

gene/protein

Amyloid beta peptide (42)

in human neurons
Drugbank entries Show/Hide entries for APP
Comment 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: 71356

gene/protein

APP

increases_quantity of

gene/protein

Amyloid beta peptide (40)

Drugbank entries Show/Hide entries for APP
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 ApoE4 constitutes the most important genetic risk factor for Alzheimer’s disease (AD), ApoE3 is neutral, and ApoE2 is protective.
Formal Description
Interaction-ID: 71365

gene/protein mutant

APOE (isoform E3)

NOT affects_activity of

disease

Alzheimer disease

if human neurons are cultured on mouse glia;
Comment ApoE4 constitutes the most important genetic risk factor for Alzheimer’s disease (AD), ApoE3 is neutral, and ApoE2 is protective.
Formal Description
Interaction-ID: 71366

gene/protein mutant

APOE (isoform E2)

decreases_activity of

disease

Alzheimer disease

if human neurons are cultured on mouse glia;
Comment 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: 100006

complex/PPI

AP-1 complex

increases_expression of

gene/protein

APP

in mouse; if cFOS is phosphorylated; AP-1 is a dimeric complex of the Jun and Fos proteins
Drugbank entries Show/Hide entries for APP
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: 124908

gene/protein mutant

APOE (isoform E3)

decreases_expression of

gene/protein

APP

compared to ApoE4
Drugbank entries Show/Hide entries for APP
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: 124909

gene/protein mutant

APOE (isoform E2)

decreases_expression of

gene/protein

APP

compared to ApoE4 and ApoeE3
Drugbank entries Show/Hide entries for APP
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 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: 124912

gene/protein mutant

APOE (isoform E3)

decreases_activity of

process

Abeta (42) secretion

in human neurons cultured on MEFs ; compared to ApoE4
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: 124913

gene/protein mutant

APOE (isoform E3)

decreases_activity of

process

Abeta (40) secretion

in human neurons cultured on MEFs ; compared to ApoE4
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: 124914

gene/protein mutant

APOE (isoform E2)

decreases_activity of

process

Abeta (42) secretion

in human neurons cultured on MEFs ; compared to ApoE4 and ApoE3
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: 124915

gene/protein mutant

APOE (isoform E2)

decreases_activity of

process

Abeta (40) secretion

in human neurons cultured on MEFs ; compared to ApoE4 and ApoE3
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: 124916

gene/protein mutant

APOE (isoform E3)

decreases_activity of

gene/protein

MAP3K12

in human neurons; compared to ApoE4; via binding to ApoE receptors
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
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: 124918

gene/protein mutant

APOE (isoform E3)

increases_quantity of

gene/protein

Amyloid beta peptide (42)

compared to ApoE2; 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: 124919

gene/protein mutant

APOE (isoform E3)

increases_quantity of

gene/protein

Amyloid beta peptide (40)

compared to ApoE2; 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: 124920

gene/protein mutant

APOE (isoform E3)

decreases_quantity of

gene/protein

Amyloid beta peptide (42)

compared to ApoE4; 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: 124921

gene/protein mutant

APOE (isoform E3)

decreases_quantity of

gene/protein

Amyloid beta peptide (40)

compared to ApoE4; 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: 124922

gene/protein mutant

APOE (isoform E2)

decreases_quantity of

gene/protein

Amyloid beta peptide (42)

compared to ApoE4 and ApoE3; 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: 124923

gene/protein mutant

APOE (isoform E2)

decreases_quantity of

gene/protein

Amyloid beta peptide (40)

compared to ApoE4 and ApoE3; unrelated to alpha-or beta-secretase expression
Comment 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: 135469

gene/protein

MAPK3

increases_phosphorylation of

gene/protein

FOS

in human neurons; if MAPK3/ERK1 is activated;
Drugbank entries Show/Hide entries for MAPK3 or FOS
Comment 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: 135470

gene/protein

MAPK1

increases_quantity of

protein modification

FOS-phos

in human neurons; if MAPK1/ERK2 is activated;
Drugbank entries Show/Hide entries for MAPK1