Viewing Schema 299

Schema Name	APOE4 toxic fragments
Accession	MS040100002.8
Gene(s)	APOE
Schema Caption	Increased risk of Alzheimer's disease via toxic fragments of APOE4
Schema Description	apoE, a key protein in lipid transport [1] 29516132 , has three primary Human isoforms, E2, E3, and E4. Compared to the most common isoform (E3), E4 confers substantially higher risk of Alzheimer’s disease: Caucasian individuals homozygous for E4 have an odds ratio of ~14 of being diagnosed with the disease compared with those homozygous for E3 [2] 9343467 . The two isoforms differ by a single SNP, the presence of which in E4 results in a missense substitution C112R. Up to 20 different mechanisms have been proposed to explain the increased risk of E4 compared with E3 [3, 4] 30844401 31367008 . This is the mechanism schema for one of the proposed mechanisms - a greater abundance of toxic apoE fragments in neurons. In the brain, under normal conditions, apoE is primarily expressed in astrocytes [1] 29516132 , and the protein is not found in neurons [5] 21741992 . apoE has been reported in neurons under some stress conditions [6, 7] 15181247 . There is also evidence that apoE in neurons is potentially subject to proteolysis, producing a range of protein fragments, and that there is a higher fragmentation level for apoE4 than apoE3 [6]. Fragments may be toxic, in two ways. First, by interacting with mitochondria, leading to impaired function/altered glucose metabolism [8] 21118811 , in turn leading impaired neutron function/cell death. Second, interaction with the cyto-skeleton. There are data suggesting a consequence of that interaction is increased p-tau [7] 29632371 , and hence, increased risk of AD. The schema defines the steps in this mechanism and provides links to the commentary and evidence evaluation. Summary conclusions: For such a long proposed and extensively studied mechanism, the supporting evidence seems surprisingly weak. Critically, it is not clear whether significant amounts of apoE are produced in neurons under any conditions encountered in vivo. In terms of the relationship of this mechanism to established facts about Alzheimer’s, in other mammals, including mice, E4 is the default allele, and so it is surprising that it would have direct toxic consequences. Studies that would most rapidly validate or otherwise this mechanism include better characterization of the iPSC derived cells (how similar to in vivo neurons are these in terms of expression profile for example), measurement of absolute expression levels, comparative studies of the molecular properties of apoE3 and E4 in mouse and human (is there some other change in the human sequence that makes the E4 allele potentially toxic, for example), and better determination of the status of apoE4 expression of human brains, particularly in the presence of Alzheimer’s.
Author(s)	John Moult
Curator(s)	John Moult
Last Modified	Sat Jan 13 2024 20:39:01 GMT-0500 (Eastern Standard Time)

Sub-state Perturbation (SSP) Annotations

Component ID: SSP2
Stage: Protein
SSP Class: Missense Variant
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: C112R
Confidence Score: 5
Comment:
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Component ID: SSP2A
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: APOE
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:

Component ID: SSP4
Stage: Protein
SSP Class: Truncated Protein
Other SSP Class:
Modifier: Increased
Ontology:
SSP Instance: APOE4 C truncated fragment
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:

Component ID: SSP5A
Stage: Complex
SSP Class: Protein-Ligand Complex Abundance
Other SSP Class:
Modifier: Increased
Ontology:
SSP Instance: Fragment-cytoskeleton
Confidence Score: 2
Comment:
For Evidence:
Against Evidence:

Component ID: SSP5B
Stage: Complex
SSP Class: Protein-Ligand Complex Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: Fragment-mitochondria
Confidence Score: 2
Comment:
For Evidence:
Against Evidence:

Component ID: SSP6A
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: P-tau
Confidence Score: 2
Comment:
For Evidence:
Against Evidence:

Component ID: SSP6B
Stage: Cell
SSP Class: Other
Other SSP Class: metabolism
Modifier: Altered
Ontology:
SSP Instance: Glucose
Confidence Score: 2
Comment:
For Evidence:
Against Evidence:

Component ID: SSP7
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease risk
Modifier: Increased
Ontology:
SSP Instance: Alzheimer's
Confidence Score: 2
Comment:
For Evidence:
Against Evidence:

Component ID: SSP3
Stage: Protein
SSP Class: Protein Dynamics
Other SSP Class:
Modifier: Altered
Ontology: NCIT
SSP Instance: APOE4
Confidence Score: 3
Comment:
For Evidence:
Against Evidence:

Component ID: SSP1
Stage: DNA
SSP Class: SNV
Other SSP Class:
Modifier: NA
Ontology: SO
SSP Instance: rs429358-C
Confidence Score: 5
Comment:
For Evidence:
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Biomarker(s) Annotations

Mechanism Module (MM) Annotations

Component ID: MM1A
Mechanism Class Name: APOE protein sythesis
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: APOE protein sythesis
Confidence Score: 2
Comment:
For Evidence:
Against Evidence:

Component ID: MM3
Mechanism Class Name:
Other Mechanism Class Name: Cleavage of APOE4
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 2
Comment:
For Evidence:
Against Evidence:

Component ID: MM4A
Mechanism Class Name:
Other Mechanism Class Name: Interaction with the cytoskeleton
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment:
For Evidence:
Against Evidence:

Component ID: MM4B
Mechanism Class Name:
Other Mechanism Class Name: Interaction with mitochondria
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment:
For Evidence:
Against Evidence:

Component ID: MM2
Mechanism Class Name:
Other Mechanism Class Name: Weaker intra-molecular interactions
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 2
Comment:
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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: MM5A
Mechanism Class Name:
Other Mechanism Class Name: tau-cytoskeleton interaction
Modifer: Decreased
Ontology: NCIT
Mechanism Instance:
Confidence Score: 1
Comment:
For Evidence:
Against Evidence:

Component ID: MM6A
Mechanism Class Name:
Other Mechanism Class Name: tau tangle formation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment:
For Evidence:
Against Evidence:

Unknown Mechanism Module (MM) Annotations

Environmental Factor Annotations

Component ID: SSP1A
Annotation Text: Neuronal Stress
Comment:
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Therapeutic Interventions Annotations

Component ID:
Annotation Text: Structure stabilizer
Comment:
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