APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants

The APOE-ε3-backbone variant W276C is protective.

“Similarly, the recently identified variant W276C was discovered in the APOE-ε3 backbone to be protective (20).”

• cites [20] Le Guen, Y. , Reil, D. , Jackson, R. J. , Peña-Tauber, A. , Khosla, C. , and Greicius, M. D. (2026) Rare APOE Missense Variants R189C and W276C Association With Risk of Alzheimer Disease. medRxiv MEDRXIV/2026/352778 sourceSupported

The APOE3*R145C substitution is detrimental and AD-risk increasing when combined with APOE-ε4.

“In contrast, the protective Christchurch variant (APOE3*R136S) (21), the detrimental AD-risk increasing APOE3*R145C substitution when combined with APOE-ε4 (22) and a second recently discovered variant in APOE3*R189C (OR = 3.35, increased risk) (20), are all in the N-terminal domain.”

• cites [22] sourceSupported

Carriers of the APOE3-backbone Jacksonville variant (V236E) have AD risk equivalent to APOE-ε2 homozygotes.

“The APOE3-backbone Jacksonville variant (V236E), located in the C-terminal coiled-coil interface, reduces ApoE self-aggregation and enhances lipidation, and carriers have AD risk equivalent to APOE-ε2 homozygotes (15,19).”

• cites [15] sourcePartly supported

  The Results section reports that APOE3-Jacksonville carriers have reduced AD risk (OR 0.10) that is “equal to or superior to” the APOE2 allele (OR 0.46). It does not compare their risk with that of APOE-ε2 homozygotes, so the specific equivalence claimed is not supported. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [19] Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups, 2022, Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease, JAMA Neurol sourcePartly supported

  The Results (page unavailable) report reduced AD risk in V236E carriers and say the ε3/ε3 (V236E) group had risk lower than or similar to the ε2/ε3 group. They do not establish equivalent risk to ε2/ε2 homozygotes, the comparator specified in the claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The Christchurch variant (APOE3*R136S) is protective.

“In contrast, the protective Christchurch variant (APOE3*R136S) (21), the detrimental AD-risk increasing APOE3*R145C substitution when combined with APOE-ε4 (22) and a second recently discovered variant in APOE3*R189C (OR = 3.35, increased risk) (20), are all in the N-terminal domain.”

• cites [21] sourcePartly supported

  The Abstract describes a PSEN1 mutation carrier with two copies of APOE3 Christchurch (R136S) whose clinical onset was delayed by nearly three decades. It calls the variant potentially protective, but says its effect may not be deterministic and other factors could have contributed. The unqualified claim that the variant is protective goes beyond this single-case evidence. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

The APOE-ε4-backbone variant R251G counterbalances the AD risk conferred by ε4 when co-inherited.

“The APOE-ε4-backbone variant R251G, also located within the C-terminal domain, counterbalances the AD risk conferred by ε4 when co-inherited (19).”

• Also stated in: § DISCUSSION · plain

  “Human genetic data show that APOE ε4*R251G counterbalances the AD risk conferred by the ε4 allele (19), and our data provide a plausible structural mechanism.”

• cites [19] Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups, 2022, Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease, JAMA Neurol sourceSupported

R251G is located in the C-terminal domain at a position predicted to lie within the oligomerization interface.

“R251G is located in the C-terminal domain at a position predicted to lie within the oligomerization interface (12), and the Arg-to-Gly substitution likely directly disrupts the intermolecular contacts that stabilize ApoE4 self-association.”

• cites [12] sourcePartly supported

  The Results and Discussion identifies the C-terminal domain as important for ApoE self-association, and residue 251 falls within that domain. It does not identify residue 251 as part of the oligomerization interface; the structure discussion says deuterium-uptake information is missing for residues 249–262. The cited paper therefore supports the domain-level location, but not the residue-specific interface prediction. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Reduced C-terminal self-association may be a shared mechanism of protection for C-terminal variants.

“Similarly W276C, which is strongly protective(20), significantly reduced signal below ApoE3 levels, mirroring the Jacksonville variant and suggesting that reduced C-terminal self-association may be a shared mechanism of protection for C-terminal variants.”

• cites [20] Le Guen, Y. , Reil, D. , Jackson, R. J. , Peña-Tauber, A. , Khosla, C. , and Greicius, M. D. (2026) Rare APOE Missense Variants R189C and W276C Association With Risk of Alzheimer Disease. medRxiv MEDRXIV/2026/352778 sourceSupported

The Arg-to-Gly substitution in R251G likely directly disrupts the intermolecular contacts that stabilize ApoE4 self-association.

“R251G is located in the C-terminal domain at a position predicted to lie within the oligomerization interface (12), and the Arg-to-Gly substitution likely directly disrupts the intermolecular contacts that stabilize ApoE4 self-association.”

• cites [12] sourcePartly supported

  The Abstract identifies residues 230–270 as an ApoE oligomerization region, supporting the cited sentence’s placement of R251G within a predicted interface. But Results and Discussion §b does not identify Arg251 among the residues implicated in self-association, and the paper does not test R251G or show that its substitution directly disrupts intermolecular contacts. That mechanism is an inference beyond the cited evidence. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

N-terminal domain interaction propagates allosterically to enhance C-terminal self-association in ApoE4.

“It is predicted that R61T disrupts the Arg61-Glu255 salt bridge responsible for ApoE4 domain interaction without altering the C-terminal sequence (11), and its normalisation of self-association to ApoE3 levels indicates that N-terminal domain interaction propagates allosterically to enhance C-terminal selfassociation in ApoE4.”

• cites [11] 2017, Molecular Mechanisms of the R61T Mutation in Apolipoprotein E4: A Dynamic Rescue, Biophys. J sourcePartly supported

  The discussion describes long-range communication and allosteric effects of mutations at residue 61 on ApoE4’s N- and C-terminal domains. The Results (p. 2196) also link R61T to weakened interdomain correlations. But the paper does not report that ApoE4’s N-terminal domain interaction enhances C-terminal self-association or that R61T normalizes self-association to ApoE3 levels. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

ApoE2's protective effects are mediated primarily through altered LDLR binding and amyloid-β clearance rather than altered self-association.

“Similarly, ApoE2 did not differ from ApoE3 in this assay, consistent with the view that ApoE2's protective effects are mediated primarily through altered LDLR binding and amyloid-β clearance rather than altered self-association (41,42).”

• cites [41] sourcePartly supported

  The Discussion reports markedly reduced LDLR binding by lipidated ApoE2 and proposes reduced receptor interactions as a protective mechanism. It only suggests that this could free LDLR to clear amyloid-β; it does not establish amyloid-β clearance as a primary mediator. The Results also report isoform-dependent aggregation, so the paper does not establish a general absence of altered self-association. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [42] sourcePartly supported

  The Biology of APOE section reports much weaker LDLR binding by APOE2 than by APOE3, and the pathological-evidence section reports that APOE2 tends to clear amyloid-β across the blood–brain barrier more efficiently. But the working model proposes hyperlipidation as a central protective mechanism; it does not establish LDLR binding and amyloid-β clearance as the primary mechanisms or compare them with APOE self-association. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Val236 is located in the C-terminal amphipathic helix that forms the core of the intermolecular coiled-coil interface.

“Val236 is located in the C-terminal amphipathic helix that forms the core of the intermolecular coiled-coil interface (10,12), and the introduction of a charged glutamate residue at this position likely disrupts hydrophobic packing.”

• cites [10] sourceNot checked — no full text of the source
• cites [12] sourcePartly supported

  In Results and Discussion, section a (page unavailable), peptide 230–243, which includes Val236, shows a change associated with ApoE self-association. Section c describes amphipathic helices in the C-terminal domain, but its listed possible helix at 238–266 does not include Val236. The paper therefore supports Val236’s location in a self-association-associated region, not the specific claim that it lies in a helix forming the core of a coiled-coil interface. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

The introduction of a charged glutamate residue at position 236 likely disrupts hydrophobic packing.

“Val236 is located in the C-terminal amphipathic helix that forms the core of the intermolecular coiled-coil interface (10,12), and the introduction of a charged glutamate residue at this position likely disrupts hydrophobic packing.”

• cites [10] sourceNot checked — no full text of the source
• cites [12] sourcePartly supported

  The Results and Discussion (section a; page unavailable) reports that replacing bulky hydrophobic residues in the C-terminal region with smaller hydrophobic or polar/charged residues can prevent oligomerization. That supports the proposed mechanism in general, but the paper does not examine a Val236-to-glutamate substitution or establish that it disrupts hydrophobic packing at that position. The citations in the printed sentence appear immediately after the preceding description of the interface, rather than after this mechanistic inference. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Small-molecule structure correctors have been shown to restore ApoE3-like behavior in iPSC-derived neurons.

“Such correctors have already been shown to restore ApoE3-like behavior in iPSC-derived neurons (37,48)”

• cites [37] sourcePartly supported

  The Discussion reports that structure correctors restored ApoE4-related functions toward ApoE3-like behavior in cultured neurons. The Experimental Procedures identify the cells as Neuro-2a and PC12 cells and primary neurons from transgenic mice, not iPSC-derived neurons; that population-specific part of the claim is unsupported. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [48] sourceSupported

The HEK293 expression system does not fully recapitulate the lipidation state or post-translational modifications of ApoE in primary astrocytes or neurons.

“Third, the HEK293 expression system does not fully recapitulate the lipidation state or post-translational modifications of ApoE in primary astrocytes or neurons”

• cites [13] sourcePartly supported

  The lipid-analysis passage (page not provided) reports no detectable lipid in HEK-secreted ApoE, unlike astrocyte-secreted lipoproteins, which contain phospholipid and cholesterol. This supports the lipidation comparison, but the paper does not establish a corresponding difference in post-translational modifications or compare HEK-secreted ApoE with neuron-secreted ApoE on either measure. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [15] sourceCould not verify

  The Results section (‘APOE3-Jac (V236E) variant reduces self-association and increases lipidation’; page unavailable) says the authors studied apoE produced in HEK293 cells and separately assessed cholesterol efflux from primary astrocytes. It does not compare HEK293-produced apoE with astrocyte- or neuron-produced apoE for lipidation or post-translational modifications. Searches for those comparisons found no passage establishing the claimed limitation. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [47] sourceCould not verify

  The Discussion and the section on mechanisms of ApoE lipidation describe cell-dependent lipidation in astrocytic and other cell systems. Our copy does not compare HEK293-expressed ApoE with ApoE from primary astrocytes or neurons, or address the claimed difference in post-translational modifications (searched: HEK293 and post-translational modifications). (LLM, conf=0.76)

  Experimental — accuracy not yet measured

ApoE lipidation shifts the monomer-oligomer equilibrium towards monomer.

“ApoE lipidation is known to shift the monomeroligomer equilibrium towards monomer (18,24,35)”

• cites [18] sourceSupported
• cites [24] sourcePartly supported

  The paper reports that monomeric ApoE4 binds lipids and, in Results > Lipid Association of ApoE4 (page not available), finds one protein per lipid-bound state. It does not show that lipidation shifts the monomer–oligomer equilibrium toward monomer; the reported equilibrium is between lipid-bound conformations, not oligomeric states. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [35] sourceSupported

ApoE2 is no different from ApoE3 in self-association.

“ApoE4 shows significantly enhanced self-association relative to ApoE3, while ApoE2 is no different from ApoE3.”

• Also stated in: § ApoE4 Shows Enhanced Self-Association Relative to ApoE3 while C-terminal Variants Show Reduced Self-Association. · plain

  “We found that ApoE2 was not different from ApoE3.”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

ApoE4 shows significantly enhanced self-association relative to ApoE3.

“ApoE4 shows significantly enhanced self-association relative to ApoE3, while ApoE2 is no different from ApoE3.”

• Also stated in: § ApoE4 Shows Enhanced Self-Association Relative to ApoE3 while C-terminal Variants Show Reduced Self-Association. · boosted

  “We found that ApoE4 constructs produced significantly greater luminescence than ApoE3 (Mann-Whitney U, p < 0.0001, Holmcorrected; Figure 2), demonstrating that ApoE4 has significantly enhanced self-association relative to ApoE3.”

• Also stated in: § CONCLUSION · plain

  “ApoE4 shows significantly enhanced self-association relative to ApoE3, driven by the ApoE4 C-terminal domain interaction.”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

The APOE ε3-backbone C-terminal variant Jacksonville (V236E) reduces ApoE self-association below ApoE3 levels.

“two APOE ε3-backbone C-terminal variants, Jacksonville (V236E) and W276C, both reduce self-association below ApoE3 levels”

• Also stated in: § ApoE4 Shows Enhanced Self-Association Relative to ApoE3 while C-terminal Variants Show Reduced Self-Association. · plain

  “Two APOE ε3-backbone protective variants, Jacksonville (V236E) (19) and W276C(20), both produced significantly less luminescence than wild-type ApoE3 (Jacksonville: p < 0.0001; W276C: p < 0.0001; Holm-corrected Mann-Whitney U; Figure 2), reducing”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

The APOE ε3-backbone C-terminal variant W276C reduces ApoE self-association below ApoE3 levels.

“two APOE ε3-backbone C-terminal variants, Jacksonville (V236E) and W276C, both reduce self-association below ApoE3 levels”

• Also stated in: § ApoE4 Shows Enhanced Self-Association Relative to ApoE3 while C-terminal Variants Show Reduced Self-Association. · plain

  “Two APOE ε3-backbone protective variants, Jacksonville (V236E) (19) and W276C(20), both produced significantly less luminescence than wild-type ApoE3 (Jacksonville: p < 0.0001; W276C: p < 0.0001; Holm-corrected Mann-Whitney U; Figure 2), reducing”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

In mixed conditioned medium containing both ApoE-SmBiT and ApoE-LgBiT, ApoE-LgBiT eluted in fractions consistent with homodimers of ApoE-LgBiT or heterodimers of ApoE-LgBiT/ApoE-SmBiT.

“We then applied HiBiT to the fractions from the SEC on mixed conditioned medium containing both ApoE-SmBiT and ApoE-LgBiT, and measured luciferase activity per fraction to detect the distribution of ApoE-LgBiT across the elution profile and found that it was similarly eluting in fractions consistent with homodimers of ApoE-LgBiT or heterodimers of ApoE-LgBiT/ApoE-SmBiT (Figure 3B).”

The African-ancestry risk variant R145C does not alter ApoE self-association relative to ApoE3.

“Meanwhile the APOE ε3-backbone variants Christchurch (R136S) (21), R145C (22), and the Admixed American risk variant R189C (20)(OR = 3.35) did not significantly alter selfassociation relative to ApoE3 (all p = ns, Holm-corrected Mann-Whitney U; Figure 2).”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

The APOE ε4-backbone protective variant R251G reduces ApoE4 self-association to the level of ApoE3.

“the APOE ε4-backbone protective variant R251G and the engineered domain-interaction probe R61T both reduce ApoE4 self-association to the level of ApoE3.”

• Also stated in: § ApoE4 Shows Enhanced Self-Association Relative to ApoE3 while C-terminal Variants Show Reduced Self-Association. · plain

  “Similarly two variants on the APOE ε4-backbone, the naturally occurring protective variant R251G (19) and the predicted mutant R61T, both restored self-association to ApoE3equivalent levels (R251G: p = ns vs ApoE3, p < 0.001 vs ApoE4; R61T: p = ns vs ApoE3, p < 0.001 vs ApoE4; Holm-corrected Mann-Whitney U; Figure 2).”

• Also stated in: § DISCUSSION · plain

  “Interestingly the protective APOE ε4-backbone variant R251G is also able to reduce the level of self-association to that of ApoE3.”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

Transfection with both SmBiT- and LgBiT-tagged versions of ApoE is necessary to generate luciferase signal.

“Transfection with both SmBiT and LgBiT tagged versions of protein was necessary to generate luciferase signal (Figure 1B).”

At the standard assay concentration (100%), ApoE3-LgBiT generated approximately 6-fold greater signal than LgBiT alone.

“At the standard assay concentration (100%), ApoE3-LgBiT generated approximately 6-fold greater signal than LgBiT alone, demonstrating that the observed luminescence is driven primarily by ApoE-ApoE interaction rather than by non-specific or spontaneous NanoBiT complementation.”

The Admixed American risk variant R189C does not alter ApoE self-association relative to ApoE3.

“Meanwhile the APOE ε3-backbone variants Christchurch (R136S) (21), R145C (22), and the Admixed American risk variant R189C (20)(OR = 3.35) did not significantly alter selfassociation relative to ApoE3 (all p = ns, Holm-corrected Mann-Whitney U; Figure 2).”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

The engineered domain-interaction probe R61T reduces ApoE4 self-association to the level of ApoE3.

“the APOE ε4-backbone protective variant R251G and the engineered domain-interaction probe R61T both reduce ApoE4 self-association to the level of ApoE3.”

• Also stated in: § ApoE4 Shows Enhanced Self-Association Relative to ApoE3 while C-terminal Variants Show Reduced Self-Association. · plain

  “Similarly two variants on the APOE ε4-backbone, the naturally occurring protective variant R251G (19) and the predicted mutant R61T, both restored self-association to ApoE3equivalent levels (R251G: p = ns vs ApoE3, p < 0.001 vs ApoE4; R61T: p = ns vs ApoE3, p < 0.001 vs ApoE4; Holm-corrected Mann-Whitney U; Figure 2).”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

The SEC profiles were similar across ApoE2, ApoE3, and ApoE4.

“These profiles were similar across ApoE2, ApoE3, and ApoE4 (Figure 3D,E).”

The luminescence signal generated is much greater for C-terminally tagged ApoE proteins than for N-terminally tagged versions.

“We found that the signal generated was much greater for C-terminally tagged versions of the proteins when compared with N-terminally tagged versions (Figure 1C) and so proceeded to use C-terminally tagged protein throughout.”

The Christchurch variant (R136S) does not alter ApoE self-association relative to ApoE3.

“Meanwhile the APOE ε3-backbone variants Christchurch (R136S) (21), R145C (22), and the Admixed American risk variant R189C (20)(OR = 3.35) did not significantly alter selfassociation relative to ApoE3 (all p = ns, Holm-corrected Mann-Whitney U; Figure 2).”

• AssumptionRests on an assumption: The NanoBiT tags fused to ApoE do not materially alter ApoE self-association.
• AssumptionRests on an assumption: Western blot-based normalization equalizes ApoE input across constructs.

ApoE3-LgBiT eluted predominantly in fractions corresponding to ∼66-106 kDa, consistent with ApoE-LgBiT eluting as a dimer or a monomer.

“ApoE3-LgBiT eluted predominantly in fractions corresponding to ∼66-106 kDa (Figure 3A), consistent with ApoE-LgBiT eluting as a dimer or a monomer.”

ApoE3-LgBiT produces a concentration-dependent increase in luminescence that substantially exceeds the signal from unfused LgBiT alone across a 256-fold concentration range.

“Across a 256fold concentration range, ApoE3-LgBiT produced a concentration-dependent increase in luminescence that substantially exceeded the signal from LgBiT alone at all concentrations tested (Figure 1D).”

ApoE-LgBiT elutes predominantly at ∼88-106 kDa across all three isoforms.

“The finding that ApoE-LgBiT elutes predominantly at ∼88-106 kDa across all three isoforms”

Jacksonville (V236E) and W276C, on an APOE3 backbone, reduce ApoE3 self-association below wild-type levels.

“Two APOE3-backbone C-terminal variants, Jacksonville (V236E) and W276C, reduce ApoE3 selfassociation below wild-type levels”

Size exclusion chromatography of ApoE-LgBiT reveals isoform-independent oligomeric distribution.

“Size exclusion chromatography of ApoE-LgBiT reveals isoform-independent oligomeric distribution.”

The oligomer/monomer ratio does not differ significantly across ApoE2, ApoE3, and ApoE4 genotypes.

“One-way ANOVA: F = 0.86, p = 0.457.”

The C-terminal self-association interface is the primary determinant of isoform-specific differences in ApoE self-association.

“Testing a panel of naturally occurring and engineered variants demonstrates that the C-terminal self-association interface is the primary determinant of isoform-specific differences:”

The observed luminescence is driven primarily by ApoE-ApoE interaction rather than by non-specific or spontaneous NanoBiT complementation.

“At the standard assay concentration (100%), ApoE3-LgBiT generated approximately 6-fold greater signal than LgBiT alone, demonstrating that the observed luminescence is driven primarily by ApoE-ApoE interaction rather than by non-specific or spontaneous NanoBiT complementation.”

The effects of Christchurch (R136S), R145C, R189C, and ApoE2 on AD risk are mediated through mechanisms independent of C-terminal self-association.

“By contrast, the Christchurch variant (R136S), R145C, R189C, and ApoE2 do not significantly alter signal relative to ApoE3, indicating that their effects on AD risk are mediated through mechanisms independent of C-terminal self-association (20)(21)(22).”

• cites (20)(21)(22)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The self-association measured here is distinct from the cysteine-dependent disulfide-linked dimers of ApoE that have been described in plasma and CSF.

“It is important to note that the self-association measured here is distinct from the cysteinedependent disulfide-linked dimers of ApoE that have been described in plasma and CSF (32,43).”

• cites [32] sourceNot checked — no full text of the source
• cites [43] 2019, Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer’s Disease, J. Alzheimers Dis. JAD sourceNot checked — no full text of the source

Plasma ApoE homodimer levels are reduced in APOEε3-carrying AD patients relative to controls.

“These cysteine-dependent ApoE3 homodimers and ApoE3-apoA-II complexes have been linked to HDL-related behavior and redox buffering (44,45), and plasma ApoE homodimer levels are reduced in APOEε3-carrying AD patients relative to controls (43), suggesting that these disulfide-linked species may themselves be functionally relevant in ways not captured by the NanoBiT assay.”

• cites [43] 2019, Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer’s Disease, J. Alzheimers Dis. JAD sourceNot checked — no full text of the source

Further reduction in self-association, as conferred by V236E or W276C, may enhance the availability of monomeric, lipid-binding-competent ApoE.

“The fact that these variants reduce signal below ApoE3 levels suggests that even the baseline level of ApoE3 self-association may be suboptimal for lipid transport, and that further reduction in self-association, as conferred by V236E or W276C, may enhance the availability of monomeric, lipid-binding-competent ApoE.”

Even the baseline level of ApoE3 self-association may be suboptimal for lipid transport.

“The fact that these variants reduce signal below ApoE3 levels suggests that even the baseline level of ApoE3 self-association may be suboptimal for lipid transport, and that further reduction in self-association, as conferred by V236E or W276C, may enhance the availability of monomeric, lipid-binding-competent ApoE.”

The data presented here support the concept that reducing ApoE4 self-association is a viable strategy for correcting ApoE4 function.

“From a therapeutic perspective, the data presented here support the concept that reducing ApoE4 self-association is a viable strategy for correcting ApoE4 function.”

The LgBiT tag potentially prevents oligomerization.

“indicates that the LgBiT tag potentially prevents oligomerization”

The enhanced self-association of ApoE4 is driven by the ApoE4 C-terminal domain interaction.

“ApoE4 shows significantly enhanced self-association relative to ApoE3, driven by the ApoE4 C-terminal domain interaction.”

The C-terminal self-association interface is an element of isoform-specific ApoE behavior.

“Together, these data establish the C-terminal self-association interface as an element of isoform-specific ApoE behavior”

Christchurch (R136S), R145C, and R189C modulate AD risk through mechanisms orthogonal to self-association.

“indicating that these variants modulate AD risk through orthogonal mechanisms.”

The isoform differences in luminescence reflect genuine differences in self-association propensity of ApoE-LgBiT to integrate into oligomers generated by the ApoE-SmBiT population.

“that the isoform differences in luminescence reflect genuine differences in self-association propensity of the ApoE-LgBiT to integrate into oligomers generated by the ApoE-SmBiT population.”

A sensitive, quantitative split-luciferase assay for ApoE self-association in serum-free conditioned medium from transfected HEK293 cells was developed.

“We have developed a sensitive, quantitative split-luciferase assay for ApoE self-association in serum-free conditioned medium from transfected HEK293 cells.”

The isoform differences reported here may represent an upper bound on the magnitude of self-association differences in a fully lipidated context.

“and the isoform differences reported here may therefore represent an upper bound on the magnitude of self-association differences in a fully lipidated context.”

The data support targeting the C-terminal self-association interface as a therapeutic strategy for ApoE4-driven AD risk.

“and support its targeting as a therapeutic strategy for ApoE4-driven AD risk.”