Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport

Probably not a substantial claim: may not pass S3 (load-bearing).

Myelin remodeling and plasticity is a continuous process in the aging brain.

“Third, myelin remodeling and plasticity is a continuous processing the aging brain (Hill et al. 2018)”

• cites Hill et al. 2018 sourceDisputed

  The Discussion distinguishes late adulthood from aging: new internodes continue to form until late adulthood, but in aging there is almost no new internode formation. It says this plasticity process comes to a halt in aging and myelin degeneration predominates, contrary to the claim that plasticity remains continuous in the aging brain. (LLM, conf=0.87)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

APOE directly binds to promoter regions of SIRT1 to promote transcription in neurons.

“Apart from direct biochemical support to sustain myelin synthesis, it was demonstrated that APOE directly binds to promoter regions of SIRT1 to promote transcription in neurons (Theendakara et al. 2016).”

• cites Theendakara et al. 2016 sourceDisputed

  The Discussion reports that ApoE binds the SirT1 promoter, but says it represses promoter activity rather than promoting transcription. In the ‘ApoE binds to the SirT1 promoter’ section, SirT1 promoter-reporter activity fell in human neuroblastoma cells expressing ApoE3 or ApoE4. (LLM, conf=0.92)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Maintenance of white matter integrity requires ongoing OPC differentiation in the aging brain.

“Recent report showed that the maintenance of white matter integrity requires such ongoing differentiation in the aging brain (Meschkat et al. 2022).”

• cites Meschkat et al. 2022 sourceDisputed

  The Introduction says OPCs generate new oligodendrocytes in adulthood, but considers it unlikely that these cells principally replace or turn over existing myelin. The Results report that OPCs did not differentiate in significant numbers during the observation period, while the study attributes loss of white matter integrity to impaired ongoing myelin synthesis, not a lack of OPC differentiation. The cited experiment was in adult mice; it does not establish a requirement for OPC differentiation in the aging brain. (LLM, conf=0.87)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Dysmyelination is seen when fatty acid synthase is specifically deleted from oligodendrocyte progenitors in a transgenic model.

“Dysmyelination was also seen when fatty acid synthase is specifically deleted from OL progenitors (OPC) in another transgenic model (Dimas et al. 2019).”

• cites Dimas et al. 2019 sourcePartly supported

  The Results section, “Depletion of fatty acid synthase in adult oligodendrocyte progenitors to study CNS remyelination” (page unavailable), confirms that Fasn was specifically ablated in adult OPCs of transgenic mice. The Results section, “Fatty acid synthesis is essential for efficient CNS remyelination” (page unavailable), reports more axons remaining demyelinated in those mutants after a spinal-cord lesion. The claim omits that injury setting and describes impaired remyelination as dysmyelination. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

On the cell surface of myelinating oligodendrocytes, LDLR and LRP1 are expressed and both receptors influence myelin formation.

“On the cell surface of myelinating OLs, at least two members of the LDLR family, LDLR and LRP1 (LDLR-related protein 1) are expressed and both receptors influence myelin formation (Zhao et al. 2007).”

• cites Zhao et al. 2007 sourcePartly supported

  The Results show LDLR expression in differentiated oligodendrocytes, and the Discussion reports earlier evidence that LRP is expressed in spinal-cord oligodendrocytes (pages unavailable). But this study measures RNA expression, not cell-surface localization, and only suggests that cholesterol uptake through these receptors may contribute to myelination; it does not establish that both receptors influence myelin formation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Cholesterol biosynthesis and its by-products are required for the initiation of axon wrapping and myelin sheet formation in zebrafish.

“The lipid supply in the myelinating process is similarly important in non-mammalian vertebrates such as zebrafish, where cholesterol biosynthesis and its by-products are required for the initiation of axon wrapping and myelin sheet formation (Mathews & Appel 2016;Mathews et al. 2014).”

• cites Mathews & Appel 2016 sourcePartly supported

  The Results section (“Cholesterol promotes axon ensheathment via Akt signaling in oligodendrocytes”; page not supplied) reports that oligodendrocytes in cholesterol-deficient zebrafish larvae did not wrap axons, while cholesterol-dependent signaling promoted membrane sheath formation. The paper does not establish that cholesterol-biosynthesis by-products are also required for wrapping or myelin sheet formation; its Discussion distinguishes cholesterol's effect on mTOR activity from protein prenylation. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Mathews et al. 2014 sourcePartly supported

  The Introduction and the results section on axon wrapping (page not provided) support a requirement for cholesterol in zebrafish axon wrapping and nascent myelin sheath formation. They assign a different role to isoprenoids, products of the same biosynthetic pathway: halting oligodendrocyte progenitor migration, not initiating axon wrapping. Thus the claim overstates what the paper says about the pathway’s by-products. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

APOE-based lipid transport in astrocytes is regulated by nuclear receptors LXR and RXR, and their activation promotes remyelination in vivo.

“APOEbased lipid transport in astrocyte is regulated by nuclear receptors LXR (Liver X Receptor) and RXR (Retinoid X Receptor) (Liang et al. 2004), and their activation promotes remyelination in vivo (Meffre et al. 2015).”

• cites Liang et al. 2004 sourceNot checked — no full text of the source
• cites Meffre et al. 2015 sourcePartly supported

  The remyelination results report that LXR activation promoted remyelination in demyelinated cerebellar slice cultures—an ex vivo model, not in vivo. The Discussion reports increased remyelinated axons in rats after treatment with an RXR ligand, but attributes that result to Franklin’s group. Thus the cited paper supports a remyelination role for the LXR/RXR pathway, but not the unqualified claim that activating both receptors promotes remyelination in vivo. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The oligodendrocyte lineage is vulnerable to amyloid plaque toxicity at different stages of their cell cycle.

“The OL lineage is vulnerable to amyloid plaque toxicity at different stages of their cell cycle (Lee et al. 2004;Desai et al. 2010)”

• cites Lee et al. 2004 sourcePartly supported

  The Results section ('Aβ and C2-ceramide are cytotoxic to OLGs'; page not provided) reports Aβ-induced death in differentiated oligodendrocyte cultures. It does not show vulnerability at different lineage or cell-cycle stages. The study tests amyloid-β peptide in culture, not plaque toxicity directly. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Desai et al. 2010 sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

APOE4 has been associated with white matter integrity loss, volume reduction, and lesion formation in the aging brain.

“APOE4 has long been associated with WM integrity loss, volume reduction and lesion formation in the aging brain (Lyall et al. 2020;Ready et al. 2011;Heise et al. 2011;Burzynska et al. 2010)”

• cites Lyall et al. 2020 sourcePartly supported

  The Abstract reports an association between APOE e4 and greater white matter hyperintensity volume, supporting the lesion component. It reports no association with brain volumes or white matter tract integrity in this cohort. The Introduction notes prior findings of atrophy and poorer integrity in pathological aging, but says evidence in non-pathological aging is less clear. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Ready et al. 2011 sourcePartly supported

  The Introduction reports an association between APOE-e4 and myelin breakdown in nondemented people, and the Discussion reports lower white matter volume in the study’s healthy midlife APOE-e4 carriers. Neither section reports an association with white matter lesion formation, so that part of the claim is unsupported by this paper. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Heise et al. 2011 sourceNot checked — no full text of the source

May combine two claims.

In Ldlr deficient mice, hypomyelination is prominent in white matter and myelin restoration from cerebral ischemia is impaired.

“In Ldlr deficient mice, hypomyelination is prominent in WM and their myelin restoration from cerebral ischemia impaired (Xie et al. 2021).”

• cites Xie et al. 2021 sourcePartly supported

  The Results (p. 11) report reduced myelination in the corpus callosum of Ldlr-deficient mice. They also report that Ldlr-deficient progenitor cells failed to alleviate ischemia-induced demyelination when transplanted into wild-type mice. That supports impaired restoration by deficient cells, but not the claim that restoration was tested in Ldlr-deficient mice after ischemia. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The sample size and power were estimated by a priori or criterion calculation using G*Power software.

“The sample size and power were estimated by A priori or Criterion calculation using G*Power software (Version 3.1.9.7, RRID:SCR_013726) (Faul et al. 2007).”

• cites Faul et al. 2007 sourcePartly supported

  The A Priori Power Analyses section says G*Power computes sample size from a required power level. The Criterion Analyses section confirms that criterion analysis is available, but says it uses a given sample size and power level to compute a decision criterion—not to estimate sample size or power. The paper supports the software and analysis-type citation, but not that description of criterion calculation. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The effects of Lrp1 on oligodendrocytes are pleiotropic on OPC differentiation in developmental and adult brain.

“The effects of Lrp1 on OLs are pleiotropic on the OPC differentiation in developmental and adult brain (Lin et al. 2017;Auderset et al. 2020).”

• cites Lin et al. 2017 sourceSupported
• cites Auderset et al. 2020 sourceSupported

May combine two claims.

APOE secreted by astrocytes in the brain are normally lipidated, but minimally lipidated or even non-lipidated form of apolipoproteins also exist to serve biological functions.

“APOE secreted by astrocytes in the brain are normally lipidated (Wahrle et al. 2004), but minimally lipidated or even non-lipidated form of apolipoproteins also exist to serve biological functions (Pedersen et al. 2009;DeMattos et al. 1998).”

• cites Wahrle et al. 2004 sourceSupported
• cites Pedersen et al. 2009 sourceNot checked — no full text of the source
• cites DeMattos et al. 1998 sourcePartly supported

  The paper reports that minimally lipidated apoE3 secreted by Neuro-2a cells stimulated neurite outgrowth without an exogenous lipid source (Apolipoprotein E secretion; introductory passage). It does not establish that non-lipidated apoE serves this function independently: the passage discussing delipidated apoE says its effects were observed only when an exogenous lipid source was added. The statement about normally lipidated astrocyte-secreted apoE is attached to a different citation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

APOE plays an essential role in transporting lipids to OLs, and this role is undermined by APOE4 genotype.

“As astrocytic support to OLs decline with age (Willis et al. 2020), we propose here that APOE plays an essential role for transporting lipids to OLs and such role will be undermined by APOE4 genotype.”

• cites Willis et al. 2020 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

External cholesterol supply in diet accelerates remyelination in demyelination models with or without reduced fatty acid synthesis.

“This is consistent with previous report that external cholesterol supply in diet accelerates the remyelination process in demyelination model with or in models with reduced fatty acid synthesis (Berghoff et al. 2017;Dimas et al. 2019).”

• cites Berghoff et al. 2017 sourcePartly supported

  The Results section reports that dietary cholesterol enhanced remyelination in a lysolecithin-induced demyelination model, and the Discussion describes improved repair in the cuprizone model. These passages support the dietary-cholesterol finding, but they do not establish its effect in a model with reduced fatty acid synthesis. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Dimas et al. 2019 sourcePartly supported

  The Results section on dietary lipids reports that a high-fat diet partially improved myelin growth in mice with reduced oligodendrocyte fatty acid synthesis. But this was developmental myelination, not remyelination after demyelination. Materials and methods states that the high-fat and standard diets contained the same percentage of cholesterol, so the paper does not show that added dietary cholesterol accelerated remyelination. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Endogenous APOE in hAPOE3 and hAPOE4 mice-derived culture, as well as purified rhAPOE3 and rhAPOE4, are minimally lipidated but biologically active.

“Importantly, it should be emphasized that the endogenous APOE in hAPOE3 and hAPOE4 mice derived culture, as well as the purified rhAPOE3 and rhAPOE4 are minimally lipidated but biologically active (DeMattos et al. 1998).”

• cites DeMattos et al. 1998 sourcePartly supported

  The Results report that apoE3 and apoE4 secreted by transfected Neuro-2a cells were poorly lipidated, and that cell-derived apoE3 stimulated neurite outgrowth. The Methods identify these as transfected cell lines, not cultures derived from hAPOE3 or hAPOE4 mice. The paper does not establish the lipidation or activity of purified recombinant apoE3 and apoE4; it reports that cell-derived apoE4 was neutral in its neurite-outgrowth assay. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

The APOE4-associated demise of OL population was confirmed in our recent report of human frontal cortex tissues, providing clinical relevance of the impact of APOE4 genotype on OL pathology.

“The APOE4 associated demise of OLs population was confirmed in our recent report of human frontal cortex tissues which provided clinical relevance of the impact of APOE4 genotype on OL pathology (Cheng et al. 2022).”

• cites Cheng et al. 2022 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Different aspects of APOE-lipid transport pathway, such as lipidation by ABCA1 or signaling of LDLR and LRP1, are required for OPC to fully differentiate after APOE stimulation.

“Different aspects of APOE-lipid transport pathway, such as the lipidation of APOE by ATP-binding cassette transporter A1 or the signaling of selective APOE receptors LDLR and LRP1), are required for OPC to fully differentiate after APOE stimulation (Zhao et al. 2007;Xie et al. 2021;Safina et al. 2016;Li et al. 2020;Auderset et al. 2020).”

• cites Zhao et al. 2007 sourcePartly supported

  The Discussion identifies LDLR and LRP as APOE-recognizing receptors, and the Introduction reports LDLR expression in mature myelinating oligodendrocytes (page numbers unavailable in our copy). The paper does not establish that ABCA1 lipidates APOE or that LDLR/LRP1 signaling is required for OPCs to fully differentiate after APOE stimulation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Xie et al. 2021 sourcePartly supported

  The Results (p. 11) report suppressed differentiation in LDLR-deficient OPCs, and the Discussion (p. 14) identifies LDLR-mediated signaling as important for oligodendroglial differentiation. The paper does not establish that this requirement occurs after APOE stimulation, nor does it test APOE lipidation by ABCA1 or LRP1 signaling. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Safina et al. 2016 sourcePartly supported

  The Results section, “Effect of ApoE4 on differentiation” (page unavailable), reports that lipid-free ApoE4 increased oligodendrocyte generation from LRP1-positive neural stem/progenitor cells, but not LRP1-knockout cells. The signaling results suggest a possible LRP1-mediated mechanism. This paper does not establish that OPCs require LRP1 signaling to fully differentiate after APOE stimulation; its experiments concern differentiation from neural stem/progenitor cells. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Cholesterol and fatty acid biogenesis play essential roles in OL differentiation and myelination.

“The biogenesis of cholesterol and fatty acids play essential role for the OL differentiation and myelination process (Nelissen et al. 2012;Dimas et al. 2019).”

• cites Nelissen et al. 2012 sourceNot checked — no full text of the source
• cites Dimas et al. 2019 sourcePartly supported

  The Discussion says oligodendrocytes depend on cholesterol synthesis for efficient myelin growth, and the Results find that endogenous fatty acid synthesis is critical for accurate myelination. But the Results section on oligodendrocyte lineage differentiation finds that FASN is not required for differentiation to CC1+ cells during postnatal development. Thus, this source supports the myelination part, not the claim that fatty acid biogenesis is essential for differentiation. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

APOE is required for transporting cholesterol-rich myelin debris away for degradation in the aged brain.

“Second, apart from cholesterol uptake, APOE is also required for transporting cholesterol-rich myelin debris away for degradation in the aged brain (Cantuti-Castelvetri et al. 2018)”

• cites Cantuti-Castelvetri et al. 2018 sourcePartly supported

  The paper (p. 1) reports that clearance of myelin debris in old mice requires cholesterol transporters including APOE. Its experiments (p. 2) show debris persisting in lysosomes of APOE-knockout cells, but describe APOE as supporting cholesterol efflux—not as transporting intact myelin debris away for degradation. The APOE-knockout lesion experiments used 12-week-old mice, so they do not directly establish APOE’s requirement in aged brains. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

No neurodegeneration was found in our hAPOE4 model at 12 months, unlike other studies reporting neuronal pathology in humanized APOE4 mice at 6 months.

“Unlike other studies reporting neuronal pathology in humanized APOE4 mice at 6 months (Leung et al. 2012;Tong et al. 2016), no neurodegeneration was found in our hAPOE4 model at 12 months.”

• cites Leung et al. 2012 sourceSupported
• cites Tong et al. 2016 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In the adult brain, myelin plasticity is a dynamic process shaped by neuronal activity and supported by ongoing OPC differentiation.

“In the adult brain, myelin plasticity exists as a dynamic process shaped by the neuronal activity (Fields 2015) that is supported by ongoing differentiation of OPCs (Franklin et al. 2020;Duncan et al. 2018).”

• cites Fields 2015 sourceSupported
• cites Franklin et al. 2020Not matched

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

• cites Duncan et al. 2018 sourceNot checked — no full text of the source

May combine two claims.

We previously showed that OL population in the frontal cortex diminishes in human dementia brain and in AD transgenic mouse model before any amyloid plaques are formed.

“Yet, we previously showed that OLs population in the frontal cortex diminish in human dementia brain and in AD transgenic mouse model before any amyloid plaques is formed (Tse et al. 2018).”

• cites Tse et al. 2018 sourceSupported

May combine two claims.

In humanized APOE mouse models, hAPOE proteins are enriched in astrocytes but minimally expressed by oligodendrocytes.

“In these models, hAPOE proteins are enriched in astrocytes but minimally expressed by OL.”

• Also stated in: § hAPOE is predominantly expressed by astrocyte in the target replacement mice · plain

  “hAPOE proteins were predominantly associated with cytoplasm of cells with astrocytic morphology across GM (cortex and hippocampus) and WM (corpus callosum).”

May combine two claims.

Lovastatin-mediated cholesterol depletion lowered general cell density in all conditions, and VLDL had minimal effects.

“Image analysis revealed that Lovastatinmediated cholesterol depletion lowered the general cell density in all conditions, and the presence of VLDL exerted minimal effects (Fig. 9C, D).”

May combine two claims.

VLDL alone rescued MBP+ cell population after Lovastatin treatment, while VLDL+rhAPOE4 alone, but not VLDL+rhAPOE3, significantly reduced MBP+ OL formation at baseline.

“In terms of mOL formation, the application of VLDL alone rescued the MBP + cell population after Lovastatin treatment, while VLDL+ rhAPOE4 alone, but not VLDL+ rhAPOE3, significantly reduced the MBP + OLs formation at the baseline level (Fig. 9E, left).”

May combine two claims.

Size of MAG+ mOLs was significantly increased by VLDL alone, VLDL+rhAPOE3, and VLDL+rhAPOE4 at baseline, and only increased by VLDL+rhAPOE4 in presence of Lovastatin.

“In contrast, the size of MAG + mOLs was significantly increased by the addition of VLDL alone, VLDL+ rhAPOE3 and VLDL+ rhAPOE4 at baseline, and only increased by VLDL+ rhAPOE4 in the presence of Lovastatin (Fig. 9F, right).”

May combine two claims.

Immunocytochemistry revealed successful differentiation of Apoe-/- OPC into myelinating Apoe-/- mOL, where the proportion of NG2+Olig2+ OPC reduced but MAG+, PLP+ and MBP+ OLs increased among the Olig2+ population at 7DIV.

“Immunocytochemistry revealed successful differentiation of Apoe -/-OPC (at 2 days in vitro (DIV)) into myelinating Apoe -/- mOL, where the proportion of NG2 + Olig2 + OPC reduced but MAG + , PLP + and MBP + OLs increased among the Olig2 + population at 7DIV (Fig. 4C).”

May combine two claims.

No statistically significant difference in age-related change or hAPOE+GFAP+ density was identified between hAPOE3 and hAPOE4 strains.

“No statistical significant difference in age-related change nor in hAPOE + GFAP + density was identified between the two strains.”

May combine two claims.

hAPOE4 genotype is significantly associated with the reduction of total OL population denoted by Olig2+ nuclei across GM regions (FCx, MCx, RSCx, and Thalamus, P = 0.0058) and WM regions (Genu, Body and Splenium of corpus callosum, Fornix and Brain Stem, P = 0.0001).

“First, hAPOE4 genotype is significantly associated with the reduction of total OL population denoted by Olig2 + nuclei across GM regions (FCx, MCx, RSCx, and Thalamus, P = 0.0058) and WM regions (Genu, Body and Splenium of corpus callosum, Fornix and Brain Stem, P = 0.0001) (Fig. 3A).”

May combine two claims.

Lovastatin significantly reduced overall MBP+ myelin sheet area but significantly increased the size of MBP+ sheet in each successfully differentiated mOL.

“Intriguingly.while the overall MBP + myelin sheet area was significantly reduced by Lovastatin, the size MBP + sheet in each of the successfully differentiated mOL cell size was significantly increased by Lovastatin.”

May combine two claims.

hAPOE+ cell density gradually increased from 6 to 12 months in both strains in cortex, corpus callosum and hippocampus, but the age-dependent increase was only statistically significant in corpus callosum.

“Full quantification showed that the hAPOE + cell density gradually increased from 6 to 12 months in both strains in the cortex, corpus callosum and hippocampus, but such age-dependent increase was only statistically significant in corpus callosum (Fig 1G).”

May combine two claims.

The diminished Olig2+ OL population and the selective spike of Nkx2.2+ pre-OL were not the consequence of developmental defects, as no significant difference was observed between hAPOE3 and hAPOE4 mouse brain at postnatal day 7.

“The diminished Olig2 + OL population and the selective spike of Nkx2.2 + pre-OL were not the consequence of developmental defects, as no significant difference was observed between hAPOE3 and hAPOE4 mouse brain at postnatal day 7 (Fig S2).”

May combine two claims.

Compared with hAPOE3, hAPOE4 triggered a significant upregulation of pro-myelinating genes including Mag, Mbp, Myrf, Plp1 and Sp7 (P < 0.0001), but exerted no effects on pro-OPC transcripts.

“Compared with hAPOE3, hAPOE4 triggered a significant upregulation of pro-myelinating genes including Mag, Mbp, Myrf, Plp1 and Sp7 (P < 0.0001), but exerted no effects on pro-OPC transcripts.”

May combine two claims.

While Lovastatin-mediated cholesterol depletion reduced the formation of MAG-expressing Oli-Neu, such defective differentiation was restored or even augmented by the presence of astrocyte co-culture, but not by astrocyte-derived condition medium.

“While Lovastatin-mediated cholesterol depletion reduced the formation of MAG-expressing Oli-Neu (Fig. 7A, B), such defective differentiation was restored or even augmented by the presence of astrocyte co-culture, but not by astrocyte-derived condition medium (Fig. 7C-L).”

May combine two claims.

In the upregulated genes, the top 15 enriched networks included eight pathways specific to nervous system integrity or function, in which three is associated with blood brain barrier.

“In the upregulated genes, the top 15 enriched networks included eight pathways specific to nervous system integrity or function, in which three is associated with blood brain barrier (Fig. 3I).”

May combine two claims.

Compared with hAPOE3, the largest reduction among GM was found in FCx (-55.4%), and in the genu (-52.6%) and fornix (-65.1%) among WM regions.

“Compared with hAPOE3, the largest reduction among GM was found in FCx (-55.4%), and in the genu (-52.6%) and fornix (-65.1%)among WM regions (Fig. 3A, B).”

May combine two claims.

Lovastatin-mediated cholesterol depletion in Apoe-/- primary OL culture was associated with a higher number of Olig2+NG2+ OPC and significantly reduced formation of MAG+ and MBP+ mOL, but not PLP+ mOL.

“Lovastatin-mediated cholesterol depletion was associated with a higher number of Olig2 + NG2 + OPC and a significantly reduced formation of MAG + and MBP + mOL, but not PLP + mOL (Fig. 8C, D).”

May combine two claims.

VLDL alone had no effect on Mbp and Mag expression; VLDL+rhAPOE3, but not VLDL+rhAPOE4, significantly increased Mbp and Mag expression; such effects were abolished by Lovastatin treatment.

“In particular, while VLDL alone has no effect on the Mbp and Mag expression, the presence of VLDL+ rhAPOE3, but not VLDL+ rhAPOE4, significantly increased Mbp and Mag expression, but such effects was abolished by the Lovastatin treatment (Fig. 9G, H).”

May combine two claims.

The cell size of individual MBP-expressing cells was significantly increased by rhAPOE4 but no difference in overall MBP+ area was found.

“The cell size of individual MBP-expressing cells was significantly increased by rhAPOE4 but no difference in overall MBP + area was found (Fig. 5C).”

May combine two claims.

hAPOE4 genotype exerted a significant effect only on the Nkx2.2+ pre-OL population in the WM, but not on the GM.

“However, hAPOE4 genotype exerted a significant effect only on the Nkx2.2 + pre-OL population in the WM (Fig. 3C), but not om the GM.”

May combine two claims.

The rescue effects were mediated only by WT astrocytes but not hAPOE4 astrocytes.

“Importantly, image analysis revealed that the rescue effects were mediated only by WT astrocytes by not hAPOE4 astrocytes, as shown in Fig. 10M-N.”

May combine two claims.

Among the downregulated genes, the top 15 enriched networks, six were associated with ATP or mitochondria-related metabolic processes and five were associated with mRNA processing with the nuclear polyadenylation-dependent mRNA catabolic process (GO:0071042) significantly enriched by 24.4 folds (FDR adjusted P-value = 0.0194).

“Among the downregulated genes, the top 15 enriched networks, six were associated with ATP or mitochondria-related metabolic processes and five were associated with mRNA processing with the nuclear polyadenylation-dependent mRNA catabolic process (GO:0071042) significantly enriched by 24.4 folds (Fig. 1D, FDR adjusted P-value = 0.0194) (Fig. 3J).”

May combine two claims.

Despite widespread reduction of Olig2+ cells, a significant increase of Nkx2.2+ OPC density was found among WM in hAPOE4 (P < 0.0001), with remarkable pairwise increases in the body (+108.1%), splenium (+73.5%) and fornix (+89.3%).

“Intriguingly, despite widespread reduction of Olig2 + cells, a significant increase of Nkx2.2 + OPC density was found among WM in hAPOE4 (P < 0.0001), with remarkable pairwise increases in the body (+108.1%),splenium (+73.5%) and fornix (+89.3%) (Fig. 3C, D).”

May combine two claims.

MBP+ myelinated area of formed mOLs was enhanced by VLDL application alone, but such effect was abolished by rhAPOE4, but not rhAPOE3.

“Similarly, the MBP + myelinated area of the formed mOLs was enhanced by VLDL application alone, but such effect was abolished by the presence of rhAPOE4, but not rhAPOE3 (Fig. 9E, right).”

May combine two claims.

Lovastatin exhibited no effects on the viability, Olig2 expression, nor proliferation at G1 and S phase during proliferation phase at any concentration.

“Lovastatin exhibited no effects on the viability (measured by DAPI density), Olig2 expression, nor proliferation at G1 (Cyclin D1, CCD1) and S phase (Cyclin A2, CCA2) during proliferation phase at any concentration (Fig. 6C, D).”

May combine two claims.

While APOE signaling components were commonly expressed by different glial cells, the APOE transporters Abca1 and Abcg1 as well as APOE receptors Lrp1 and Vldlr were highly enriched in OPCs in frontal cortex of WT mice.

“While APOE signaling components were commonly expressed by different glial cells, the APOE transporters Abca1 and Abcg1 as well as APOE receptors Lrp1 and Vldlr were highly enriched in OPCs (polydendrocyte) in frontal cortex of the WT mice (Fig. S1).”

May combine two claims.

In our hAPOE4 model, minimal changes were found among MAG, MBP, and PLP expression, but unaltered myelin fiber density coincided with an increase of FluoroMyelin signal.

“In our hAPOE4 model, minimal changes were found among the three key myelin sheath specific protein expression (MAG, MBP and PLP), but such unaltered myelin fiber density coincided with an increase of FluoroMyelin signal in hAPOE4 mice.”

May combine two claims.

Restorative efforts were abolished by pretreatment with recombinant human APOE4, but not APOE3.

“Of note, these restorative efforts were abolished by the pretreatment of recombinant human APOE4, but not APOE3 proteins.”

May combine two claims.

The Olig2+ total OL population and MBP+ mOL population were significantly reduced in Apoe-/- OLs.

“The Olig2 + total OL population and MBP + mOL population were significantly reduced in Apoe -/-OLs.”

May combine two claims.

Cholesterol is essential for OPC to differentiate but not proliferate.

“In the latter, we clearly showed that cholesterol is essential for OPC to differentiate but not proliferate.”

May combine two claims.

In primary cell culture, cholesterol synthesis inhibition or APOE deficiency alike jeopardize OL differentiation.

“In primary cell culture, cholesterol synthesis inhibition or APOE deficiency alike jeopardize OLs differentiation.”

May combine two claims.

In Apoe-/- OPCs, non-lipidated rhAPOE4 induces no difference in total MBP+ myelinated area or individual MBP+ cell size.

“No difference was found in the total MBP + myelinated area, nor individual MBP + cell size was induced by hAPOE4.”

May combine two claims.

Lovastatin had no effects on the formation of PLP+ mOL nor the signal intensity of MBP immunoreactivities.

“Lovastatin had no effects on the formation of PLP + mOL nor the signal intensity of MBP immunoreactivities.”

May combine two claims.

In Apoe-/- primary oligodendrocyte culture, the Olig2+ total OL population and MBP+ mOL population are significantly reduced compared to wildtype.

“The Olig2 + total OL population and MBP + mOL population were significantly reduced in Apoe -/-OLs.”

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.

After 7DIV differentiation, Apoe-/- derived mOLs show significantly increased expression of myelin proteins MBP, MAG and PLP.

“After the 7DIV differentiation, mOL with myelin protein (MBP, MAG and PLP) expression was significantly increased”

May combine two claims.

No difference was found in total MBP+ myelinated area, nor individual MBP+ cell size was induced by hAPOE4.

“No difference was found in the total MBP + myelinated area, nor individual MBP + cell size was induced by hAPOE4.”

May combine two claims.

Transwell co-culture with hAPOE4 astrocytes significantly increases Oli-Neu differentiation in normal condition but does not restore the inhibitory effects of Lovastatin.

“Transwell co-culture with hAPOE4 astrocyte significantly increased Oli-Neu differentiation in normal condition but did not restore the inhibitory effects of Lovastatin”

May combine two claims.

No significant difference was found in the corresponding total MBP myelinated area nor individual MBP+ cell size.

“No significant difference was found in the corresponding total MBP myelinated area nor individual MBP + cell size.”

May combine two claims.

In hAPOE4 mice at 12 months, there is an overall significant increase in area double-positive for FluoroMyelin and MBP compared to hAPOE3 (P = 0.0001), with a significant pairwise increase at the fornix (P = 0.005).

“hAPOE4 contributed to an overall significant increased area positive for FluoroMyelin (P = 0.0087) and double-positive for FluoroMyelin and MBP (P = 0.0001) across brain regions, with a pair-wise significant increase at the fornix (P = 0.005”

May combine two claims.

In transwell co-culture, while Lovastatin abolishes Oli-Neu differentiation, the presence of wildtype astrocytes restores MAG expressing Oli-Neu formation.

“While Lovastatin abolished Oli-Neu differentiation, the presence of wildtype astrocytes in transwell co-culture restored the MAG expressing Oli-Neu formation”

May combine two claims.

VLDL alone significantly restored MAG+ mOL density during cholesterol depletion, but such effect was similarly suppressed by rhAPOE3-VLDL and rhAPOE4-VLDL.

“However, pairwise quantification of MAG + Olig2 + immunocytochemistry revealed that VLDL alone significantly restored MAG + mOL density during cholesterol depletion, but such effect was similarly suppressed by rhAPOE3-VLDL and rhAPOE4-VLDL.”

May combine two claims.

In Apoe-/- OL culture during cholesterol depletion, VLDL alone significantly restores MAG+ mOL density, but this effect is suppressed by rhAPOE3-VLDL and rhAPOE4-VLDL.

“VLDL alone significantly restored MAG + mOL density during cholesterol depletion, but such effect was similarly suppressed by rhAPOE3-VLDL and rhAPOE4-VLDL.”

May combine two claims. The quote only partly states this claim.

No pathological change nor density change was observed in the cortex, corpus callosum and hippocampus for Olig2+ and Nkx2.2+ populations in hAPOE4 mouse pup at postnatal day 7.

“No pathological change nor density change was observed in the cortex, corpus callosum and hippocampus with the quantification shown in C.”

May combine two claims.

In hAPOE3 and hAPOE4 mice, GFAP immunohistochemistry shows no signs of astrogliosis, with no statistically significant difference in GFAP+ area across cortex, corpus callosum and hippocampus.

“Immunohistochemistry of GFAP alone showed no signs of astrogliosis hAPOE3 and hAPOE4, as confirmed by no statistical significance in GFAP+ area across cortex, corpus callosum and hippocampus”

May combine two claims.

In Apoe-/- OPCs treated with Lovastatin, VLDL and rhAPOE-VLDL have no significant effects on total cell density or Olig2+ OL population.

“but VLDL and rhAPOE-VLDL had no significant effects.”

May combine two claims.

In Apoe-/- primary OL culture, Lovastatin significantly reduces MAG+ mOL and reduces the number and areas of MBP+ mOL.

“but significantly reduced MAG + mOL and reduced the number and areas of MBP + mOL.”

May combine two claims.

In hAPOE3 and hAPOE4 mouse cerebrum, hAPOE immunoreactivity in these cells colocalizes with astrocytic marker GFAP but not with OL lineage marker Olig2.

“The hAPOE-IR (green) in these cells readily colocalize with astrocytic marker GFAP (red), but not OL lineage marker Olig2 (blue).”

May combine two claims.

In Apoe-/- primary OL culture, Lovastatin has no effects on the formation of PLP+ mOL nor the signal intensity of MBP immunoreactivities.

“Lovastatin had no effects on the formation of PLP + mOL nor the signal intensity of MBP immunoreactivities.”

May combine two claims.

In hAPOE4 mice, there is an overall reduction of Olig2+ oligodendrocyte density in gray matter (P = 0.0409) and white matter (P = 0.0001), with major pairwise reduction between hAPOE3 and hAPOE4 in genu (P = 0.0028) and fornix (P = 0.0052).

“hAPOE4 contributed to an overall reduction of Olig2 + OL density in the GM (left, P = 0.0409) and WM (right, P = 0.0001) where major pairwise reduction was seen between hAPOE3 and hAPOE4 in genu (P = 0.0028) and fornix (P = 0.0052).”

May combine two claims.

In hAPOE4 vs hAPOE3 frontal cortex, there is a significant downregulation of pro-OPC gene Hes5 and a significant upregulation of pro-myelinating genes Mag, Myrf, Plp and Sp7.

“a significant downregulation of pro-OPC gene Hes5, but a significant upregulation of pro-myelinating gene Mag, Myrf, Plp and Sp7 was identified”

• cites Sock & Wegner 2019 sourceNot checked — no full text of the source

May combine two claims.

In differentiated Apoe-/- mOLs, there is no significant difference in total MBP myelinated area or individual MBP+ cell size.

“No significant difference was found in the corresponding total MBP myelinated area nor individual MBP + cell size.”

May combine two claims.

In Apoe-/- OPCs treated with Lovastatin, Lovastatin exerts overall negative effects on total cell density (P <0.0001) and Olig2+ OL population (P = 0.0008).

“Lovastatin exerted overall negative effects on total cell density (P <0.0001) and Olig2 + OL population (P = 0.0008)”

May combine two claims.

In Oli-Neu cells at proliferative state, Lovastatin treatment has no effects on cell density or Olig2 expression.

“Quantification of Oli-Neu cells at proliferative state showed no effects on cell density or Olig2 expression upon Lovastatin treatment.”

May combine two claims.

In hAPOE3 and hAPOE4 mouse cerebrum at 6 months, human APOE immunoreactivity is detected across all regions, but not in wildtype.

“hAPOE-IR was detected across all regions in hAPOE3 and hAPOE4 but not WT.”

May combine two claims.

Lovastatin exerted overall negative effects on total cell density and Olig2+ OL population, but VLDL and rhAPOE-VLDL had no significant effects.

“Lovastatin exerted overall negative effects on total cell density (P <0.0001) and Olig2 + OL population (P = 0.0008), but VLDL and rhAPOE-VLDL had no significant effects.”

May combine two claims.

In Apoe-/- OL culture, the presence of VLDL alone increases the formation of mOL and their MBP+ sheet formation, but this is abolished by the presence of rhAPOE4 with or without Lovastatin.

“The presence of VLDL alone increased the formation of mOL and their MBP + sheet formation, but it was abolished by the presence of rhAPOE4 with or without Lovastatin.”

May combine two claims.

The presence of VLDL alone increased the formation of mOL and their MBP+ sheet formation, but it was abolished by the presence of rhAPOE4 with or without Lovastatin.

“The presence of VLDL alone increased the formation of mOL and their MBP + sheet formation, but it was abolished by the presence of rhAPOE4 with or without Lovastatin.”

The quote only partly states this claim.

In hAPOE3 and hAPOE4 mice at 12 months, NeuN immunohistochemistry reveals no observable difference between hAPOE3 and hAPOE4 despite alteration in myelin density.

“Immunohistochemistry-immunofluorescence of NeuN (green), a general neuronal marker, revealed no observable difference between hAPOE3 and hAPOE4 despite the alteration in myelin density.”

May combine two claims.

The transwell co-culture, but not condition medium, contributes to an overall change of MAG Oli-Neu formation (P = 0.0056).

“The transwell co-culture, but not condition medium, contributed to an overall change of MAG Oli-Neu formation (P = 0.0056).”

May combine two claims.

In differentiating Oli-Neu cells, Lovastatin treatment reduces MAG+ mOL formation and significantly increases cell size.

“Quantification of MAG + Oli-Neu cells formation, and the length of MAG + cellular process upon Lovastatin treatment showed a reduction of mOL formation with a significantly increased cell size”

May combine two claims.

Lovastatin significantly increased Olig2 and NG2+ OPC population but significantly reduced MAG+ mOL and reduced the number and areas of MBP+ mOL.

“Lovastatin signficantly increased Olig2 and NG2 + OPC population but significantly reduced MAG + mOL and reduced the number and areas of MBP + mOL.”

May combine two claims.

In hAPOE4 mice at 12 months, hAPOE4 significantly reduces MOG expression across brain regions (P = 0.0013), with a significant pairwise reduction in the genu of the corpus callosum by 32.2% (P=0.0095).

“hAPOE4 significantly reduced MOG expression across brain regions (P = 0.0013, Two-Way ANOVA with Šídák's multiple comparisons test) with a significant pairwise reduction in the genu of the corpus callosum (by 32.2%, P=0.0095).”

Probably not a substantial claim: may not pass S3 (load-bearing).

When squalene synthase is selectively ablated in oligodendrocytes, young transgenic animals exhibit severe myelin loss with ataxic phenotype.

“When squalene synthase, a key enzyme in cholesterol biosynthesis, is selectively ablated in OLs, young transgenic animals exhibit severe myelin loss with ataxic phenotype (Saher et al. 2005).”

• cites Saher et al. 2005 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Myelin loss is accelerated with cognitive impairments.

“such myelin loss is accelerated with cognitive impairments (Bartzokis et al. 2007).”

• cites Bartzokis et al. 2007 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

The susceptibility of oligodendrocytes in Alzheimer's disease may be related to their sensitivity to oxidative DNA damage.

“The susceptibility of OLs in AD may be related to their sensitivity to oxidative DNA damage (Tse et al. 2021)”

• cites Tse et al. 2021 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Lipid depositions in myelin account for more than three quarters of all free cholesterol in the brain.

“The lipid depositions in myelin are so heavy that accounts for more than three quarters of all free cholesterol in the brain (Saher & Stumpf 2015).”

• cites Saher & Stumpf 2015 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

APOE4 is the strongest genetic risk factor for sporadic Alzheimer's disease.

“APOE4 (Apolipoprotein E allele ε4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD).”

• Also stated in: § 1. INTRODUCTION · plain

  “the strongest genetic risk factor of sporadic AD, APOE4 allele (single nucleotide polymorphism variant of Apolipoprotein E ε4) (Michaelson 2014).”

• cites Michaelson 2014 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Myelin content in the frontal lobe begins to decline in the fourth decade in the aging brain.

“Functional magnetic resonance imaging (fMRI) studies identified that the myelin content in the frontal lobe begins to decline in the fourth decade in the aging brain (Bartzokis 2004)”

• cites Bartzokis 2004 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

White matter abnormalities emerge as early findings in the aging brain and sporadic Alzheimer's disease.

“White matter (WM) abnormalities emerge as early findings in the aging brain and sporadic Alzheimer's disease (AD) (Amlien & Fjell 2014;Bartzokis 2004;Medina et al. 2006).”

• cites Amlien & Fjell 2014 sourceNot checked — no full text of the source
• cites Bartzokis 2004 sourceNot checked — no full text of the source
• cites Medina et al. 2006 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Oli-Neu is not a commonly misidentified cell line by ICLAC, and it was directly obtained by the creator Dr Trotter.

“Oli-Neu is not a commonly misidentified cell line by ICLAC, and it was directly obtained by the creator Dr Trotter.”

May combine two claims.

hAPOE is selectively expressed by astrocytes, but not oligodendrocytes, in the knock-in strains, and this expression pattern is highly similar between hAPOE3 and hAPOE4 animals in the aging brain.

“These histological findings suggested that hAPOE is selectively expressed by astrocytes, but not OLs, in the knock-in strains and such expression pattern was highly similar between hAPOE3 and hAPOE4 animals in the aging brain.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

For each animal experiment, at least four animals were analyzed per group with both male and female included.

“For each animal experiment, at least four animals were analyzed per group with both male and female included.”

Probably not a substantial claim: may not pass S3 (load-bearing).

No randomization was performed to allocate animal subjects in the study.

“No randomization was performed to allocate animal subjects in the study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

For all image-based experiments, the experimenters were blinded against the conditions during image analysis and the quantifications in QuPath.

“For all image-based experiments, the experimenters were blinded against the conditions during image analysis and the quantifications in QuPath.”

Probably not a substantial claim: may not pass S3 (load-bearing).

At least three independent experiments were conducted.

“In any case, at least three independent experiments were conducted”

May combine two claims.

Endogenous APOE is at least partially required for the formation of mOLs, and the endogenous expression of hAPOE3 or hAPOE4 does not implicate on OL formation during normal development.

“These results indicated that endogenous APOE is at least partially required for the formation of mOLs, and the endogenous expression of hAPOE3 or hAPOE4 does not implicate on OL formation during normal development.”

May combine two claims.

An APOE-mediated interaction between astrocytes and oligodendrocyte lineage exists in the cerebrum, and the major source of APOE in the cerebrum is likely astrocytes.

“These findings suggested that an APOE-mediated interaction between astrocytes and OL lineage exists in the cerebrum, and major source of APOE in the cerebrum is likely astrocytes.”

Classified as probably not a substantial claim. May combine two claims.

hAPOE4 compromised myelin integrity and triggered a cellular response to remyelinate.

“Based on the putative shift in lipid-protein composition of the myelin fibers and the enhanced commitment to differentiation in the overall diminished OL population, it is conceivable to propose that hAPOE4 compromised myelin integrity and triggered a cellular response to remyelinate.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Samples without primary antibodies incubation served as negative controls.

“Samples without with primary antibodies incubation omitted served as negative controls.”

May combine two claims.

Nkx2.2 is a specific transcription factor transiently expressed by late OPC before terminal differentiation into mOLs and diminished upon maturation.

“Nkx2.2 is the specific transcription factor transiently expressed by late OPC before its terminal differentiation into mOLs and then diminished when the maturation is completed (Zhu et al. 2014).”

• cites Zhu et al. 2014 sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

The increased FluoroMyelin signal may represent increased turnover or breakdown of myelin fibers, or both.

“FluoroMyelin is a lipophilic dye that binds to intact and degraded myelin lipids, the increased signal may represent the consequences of increased turnover or breakdown of myelin fibers or both.”

May combine two claims.

Endogenous APOE function is required for mature MBP+ OL formation, while intrinsic hAPOE3 or hAPOE4 has no implication on OL development.

“The direct comparison between primary OLs derived from WT, Apoe -/-, hAPOE3 and hAPOE4 mice suggested that endogenous APOE function is required for mature MBP + OL formation, while the presence of intrinsic hAPOE3 or hAPOE4 has no implication on OL development.”

May combine two claims.

APOE-lipid complex released from astrocytes is taken up by differentiating OL especially when cholesterol synthesis capacity is limited, and hAPOE4 jeopardizes such extrinsic support.

“Importantly, our co-culture experiment clearly demonstrated that APOElipid complex released from astrocytes are taken up by differentiating OL especially when their cholesterol synthesis capacity is limited, and hAPOE4 will jeopardize such extrinsic support.”

May combine two claims.

APOE4 exerts a direct impact on OL, and probably subsequent WM abnormalities.

“The present study provides the proof-of-concept evidence that suggest APOE4 exert a direct impact on OL, and probably the subsequent WM abnormalities.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The lack of profound effects of rhAPOE4-lipids on MAG accentuates the unique functions of MBP in rearranging the cholesterol-rich plasma membrane during compact myelin formation.

“Besides, the lack of profound effects of rhAPOE4-lipids on MAG accentuate the unique functions MBP in rearranging the cholesterol-rich plasma membrane during compact myelin formation (Baron & Hoekstra 2010;Fitzner et al. 2006).”

• cites Baron & Hoekstra 2010 sourceNot checked — no full text of the source
• cites Fitzner et al. 2006 sourceNot checked — no full text of the source

May combine two claims.

Surviving OL population in APOE4 carriers remains functional but is likely debilitated by disproportionate myelination demands and compromised astrocyte support.

“The surviving OL population in APOE4 carriers remain functional but likely debilitated by the disproportionate demands for myelination and the compromised support from astrocytes.”

May combine two claims.

Humanized APOE transgenic mouse models similarly generate AD-like phenotypes at transcription, metabolism, and pathology levels, with signs of cognitive impairments.

“These models similarly generated AD-like phenotypes at the transcription, metabolism, and pathology level (Hamanaka et al. 2000;Mann et al. 2004;Preuss et al. 2020;Fitz et al. 2020) with signs of cognitive impairments (Leung et al. 2012;Tong et al. 2016).”

• cites Hamanaka et al. 2000Not matched

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

• cites Mann et al. 2004Not matched

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

• cites Preuss et al. 2020Not matched

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

Probably not a substantial claim: may not pass S4 (based).

APOE4 allele is associated with WM abnormalities in healthy aging population and AD patients.

“APOE4 allele is associated with WM abnormalities in healthy aging population and AD patients.”

May combine two claims.

The accumulation of Nkx2.2+ OPC amid reduced Olig2+ population and unchanged CC1+ mOLs indicates that the OL differentiation program is interrupted by hAPOE4.

“The accumulation of Nkx2.2 + OPC in the midst of reduced Olig2 + population and unchanged CC1 + mOLs indicated that the OL differentiation program is interrupted by hAPOE4.”

May combine two claims.

APOE4 impairs OL differentiation by interfering with lipid uptake in a humanized APOE4 mouse model without amyloid cascade transgenes, in vivo and in vitro.

“Here, we further established that APOE4 implicates on OL differentiation by interfering lipid uptake in a well-established humanized APOE4 mouse model without any transgenic mutation along amyloid cascade hypothesis in vivo and in vitro.”

May combine two claims.

The heavily reduced OL population in hAPOE4 is likely responsible for maintaining the largely unaltered pool of myelin proteins, which might lead to exhaustion at a faster rate.

“The heavily reduced OL population in hAPOE4 is likely responsible for maintaining the largely unaltered pool of myelin proteins that might lead to exhaustion at a faster rate.”

May combine two claims.

Extrinsic hAPOE4 is likely to inhibit mOL formation, with regional specificity observed.

“Finally, while extrinsic hAPOE4 is likely to inhibit mOL formation, regional specificity was observed.”

May combine two claims.

In hAPOE4 co-culture, hAPOE is detected in cell body and cellular processes of differentiating Oli-Neu cells under normal and Lovastatin-treated conditions, suggestive of uptake of hAPOE-lipid.

“In hAPOE4 co-culture, hAPOE was detected in cell body (arrowheads) and the cellular processes (open arrowheads), suggestive of uptake of hAPOElipid in differentiating Oli-Neu cells under K normal and L Lovastatin-treated condition.”