MecCog

Schema Name	Increased Alzheimer's risk in the presence of apoE4 as the result of lower endosome pH
Accession	MS060700010.5
Gene(s)	apoE, lrp1,app
Schema Caption	Reduced endocytosis of Abeta in the presence of apoE4 results in increased extracellular Abeta concentration and hence an increased rate of amyloid plaque formation.
Schema Description	The APOE4 allele leads to lower endosomal pH and as a result less endocytosis and clearance of Abeta by astrocytes. Lower endosomal pH is the result of lower abundance of membrane channel protein, NHE6 which provides an escape route for protons from the endosome, so normally helping to maintain a higher pH. Lower NHE6 abundance is a result of lower expression of the corresponding gene, in turn caused by increased nuclear abundance of a histone deacetylase, HDAC4. The mechanism by which HDAC4 nuclear abundance is increased is not clear, but may involve inhibition of protein kinase C by apoE4. Lower endosome pH results in impaired recycling of the cell surface receptor LRP1. One of the functions of LRP1 is import of A, allowing its subsequent degradation. Thus Abeta clearance is impaired, increasing risk of Alzheimer’s.
Author(s)	John Moult
Curator(s)	John Moult
Last Modified	Tue Dec 05 2023 11:57:13 GMT-0500 (Eastern Standard Time)

Sub-state Perturbation (SSP) Annotations

Component ID: SSP1
Stage: DNA
SSP Class: SNV
Other SSP Class:
Modifier: NA
Ontology: SO_v20210216
SSP Instance: rs429358-C
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:

Component ID: SSP2
Stage: Protein
SSP Class: Other
Other SSP Class: Missense variant
Modifier: NA
Ontology:
SSP Instance: C112R
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:

Component ID: SSP3
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES_v20170921
SSP Instance: Nuclear HDAC4
Confidence Score: 3
Comment: In brain astrocytes expressing APOE4 there is a higher abundance of HDAC4, a histone deacetylase, in the nucleus.
For Evidence: PMID:29946028, PMID:25972179
Against Evidence:

Component ID: SSP4
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES_v20170921
SSP Instance: NHE6
Confidence Score: 3
Comment: There are lower levels of NHE6 protein in astrocyte endosomes in the presence of apoE4 compared with apoE3.
For Evidence: PMID:29946028, PMID:16198584
Against Evidence:

Component ID: SSP5
Stage: Cell
SSP Class: Other
Other SSP Class: pH
Modifier: Decreased
Ontology:
SSP Instance: endosomes
Confidence Score: 3
Comment: In vivo, the pH of astrocyte endosomes is lower in apoE4 expressing astrocytes than apoE3 ones.
For Evidence: PMID:29946028
Against Evidence:

Component ID: SSP6A
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES_v20170921
SSP Instance: Astrocyte surface LRP1
Confidence Score: 3
Comment: There is a lower abundance of the LRP1 receptor on the surface of astrocytes expressing APOE4 compared with APOE3.
For Evidence: PMID:29946028
Against Evidence:

Component ID: SSP7
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES_v20170921
SSP Instance: Extracellular Abeta
Confidence Score: 3
Comment: Interstitial Ab abundance is higher in E4 human brains than for E3.
For Evidence: PMID:29946028
Against Evidence:

Component ID: SSP8
Stage: Protein
SSP Class: Other
Other SSP Class: Aggregation
Modifier: Increased
Ontology:
SSP Instance: Amyloid plaque
Confidence Score: 3
Comment:
For Evidence:
Against Evidence:

Component ID: SSP9
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease risk
Modifier: Increased
Ontology:
SSP Instance: Alzheimer's
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:

Biomarker(s) Annotations

Mechanism Module (MM) Annotations

Component ID: MM1
Mechanism Class Name:
Other Mechanism Class Name: Protein synthesis
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:

Component ID: MM3
Mechanism Class Name:
Other Mechanism Class Name: Histone acetylation
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment:
For Evidence:
Against Evidence:

Component ID: MM4
Mechanism Class Name:
Other Mechanism Class Name: Proton escape from endosomes
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment:
For Evidence:
Against Evidence:

Component ID: MM5
Mechanism Class Name:
Other Mechanism Class Name: Decreased LRP1 recycling
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: Decreased endosomal pH, in turn caused by lower abundance of NHE6, results in less recycling of LRP1 to the cell surface.
For Evidence: PMID:29946028
Against Evidence:

Component ID: MM6A
Mechanism Class Name:
Other Mechanism Class Name: less Abeta endocytosis
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: In the presence of apoE4 there is a lower rate of Ab import into astrocytes compared with apoE3.
For Evidence: PMID:29946028
Against Evidence:

Component ID: MM7
Mechanism Class Name:
Other Mechanism Class Name: Higher rate of plaque formation
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment:
For Evidence:
Against Evidence:

Component ID: MM8
Mechanism Class Name:
Other Mechanism Class Name: Down steam processes
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:

Unknown Mechanism Module (MM) Annotations

Component ID: MM2
Comment:
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Environmental Factor Annotations

Therapeutic Interventions Annotations