Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol

May combine two claims.

Ch25h is overexpressed in AD brain and in mouse models of amyloid deposition and tau-mediated neurodegeneration.

“We have recently demonstrated that Ch25h is overexpressed in AD brain as well as in mouse models of amyloid deposition and tau-mediated neurodegeneration (8).”

• cites [8] Wong, 2020, 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner, J. Neuroinflam. sourceSupported

May combine two claims.

25HC disrupts hippocampal plasticity and learning in mice.

“More recently, we showed that 25HC disrupts hippocampal plasticity and learning in mice (16) suggesting that 25HC may also exhibit neuron-specific activities.”

• cites [16] Izumi, 2021, A Proinflammatory stimulus disrupts hippocampal plasticity and learning via microglial activation and 25-hydroxycholesterol, J. Neurosci. sourcePartly supported

  The Results report that 25HC inhibited hippocampal LTP in mouse slices. They also report that LPS impaired learning in wild-type mice but not in Ch25h knockout mice; the Introduction says this suggests 25HC contributes to impaired learning. The paper does not directly show that administering 25HC disrupts learning in mice, so the claim states that part more definitively than the evidence supports (page numbers unavailable). (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Activation of primary microglia with LPS upregulates Ch25h and increases synthesis and release of 25HC into the extracellular milieu.

“Activation of primary microglia with the toll-like receptor-4 agonist, lipopolysaccharide (LPS) also upregulates Ch25h and results in increased synthesis and release of 25HC into the extracellular milieu (8).”

• cites [8] Wong, 2020, 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner, J. Neuroinflam. sourceSupported

May combine two claims.

Astrocytes are important for cholesterol synthesis in the brain and are a major source of ApoE-containing lipoprotein particles central to cholesterol transport between astrocytes, neurons, and other cells.

“As astrocytes are important for cholesterol synthesis in brain and are a major source of ApoE-containing lipoprotein particles central to cholesterol transport between astrocytes, neurons, and other cells (17)”

• cites [17] Staurenghi, 2021, Cholesterol Dysmetabolism in Alzheimer’s Disease: a starring role for astrocytes, Antioxidants (Basel) sourceSupported

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

ApoE markedly accelerates amyloid deposition and tau-mediated neurodegeneration in mouse models.

“ApoE also markedly accelerates amyloid deposition (23,24) as well as taumediated neurodegeneration in mouse models (25).”

• cites [23] Ulrich, 2018, ApoE facilitates the microglial response to amyloid plaque pathology, J. Exp. Med. sourcePartly supported

  In “ApoE modifies Aβ deposition” (page unavailable), the paper reports strongly reduced fibrillar amyloid burden in Apoe-deficient mice, supporting a role for ApoE in amyloid formation. But total Aβ deposition increased without ApoE in one mouse model and did not significantly differ in another, so the unqualified claim that ApoE markedly accelerates amyloid deposition overstates these results. The tau-mediated neurodegeneration clause has a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [24] Liu, 2017, ApoE4 Accelerates Early Seeding of Amyloid Pathology, Neuron sourceSupported
• cites [25] Shi, 2017, ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy, Nature sourceSupported

May combine two claims.

Loss of Ch25h and 25HC promotes IL-1β production in mouse macrophages, whereas 25HC amplifies IL-1β secretion in an ApoE-dependent manner in mouse microglia.

“While loss of Ch25h and 25HC promoted interleukin 1-beta production in mouse macrophages (14,15), 25HC amplified interleukin 1-beta secretion in an ApoEdependent manner in mouse microglia (8).”

• cites [14] Reboldi, 2014, Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon, Science sourceSupported
• cites [15] Dang, 2017, Oxysterol restraint of cholesterol synthesis prEvents AIM2 inflammasome activation, Cell sourceSupported
• cites [8] Wong, 2020, 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner, J. Neuroinflam. sourceSupported

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

A single copy of APOE-E4 confers ~3.7 times greater risk than APOE-E3, and homozygous APOE-E4/E4 carriers have ~12-15 times greater risk for developing AD.

“A single copy of the APOE-E4 allele confers a ∼ 3.7 times greater risk than the common variant, APOE-E3, whereas homozygous APOE-E4/E4 carriers have a ∼12-15 times greater risk for developing AD.”

• cites [18] Yamazaki, 2019, Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies, Nat. Rev. Neurol. sourcePartly supported

  The Introduction says one APOE ε4 allele increases late-onset AD risk 3–4-fold, consistent with approximately 3.7-fold. For two alleles, it reports 9–15-fold, not the claimed 12–15-fold, and limits these estimates to late-onset AD. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

APOE is the most important risk factor for AD and contributes significantly to risk of several other neurological and nonneurological disorders.

“APOE is the most important risk factor for AD and contributes significantly to the risk of developing several other neurological and nonneurological disorders (18).”

• cites [18] Yamazaki, 2019, Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies, Nat. Rev. Neurol. sourcePartly supported

  The Introduction calls APOE polymorphism a major risk determinant of late-onset AD and links APOE genotype to the risk of other neurological disorders, including dementia with Lewy bodies and Parkinson disease dementia. The Biology of APOE section links APOE2 to type III hyperlipoproteinaemia and APOE4 to pro-atherogenic changes. The paper does not establish that APOE is the *most important* risk factor for AD generally, or that it significantly affects the risk of *several* nonneurological disorders. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Ch25h expression has been reported in primary cultured astrocytes.

“However, expression of Ch25h has also been reported in primary cultured astrocytes (36)”

• cites [36] Berghoff, 2020, Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis, Nat. Neurosci. sourceCould not verify

  The Results section, “The origin of cholesterol for remyelination depends on the disease phase,” discusses sterol-gene expression in astrocytes isolated from mice, not Ch25h expression in primary cultured astrocytes. Searches for “Ch25h” and “cholesterol 25-hydroxylase astrocyte culture” found no passage addressing that claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

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

The low Soat2 expression levels and higher Soat1 expression levels agree with publicly available databases for expression of these genes in astrocytes in the brain.

“The low Soat2 expression levels and higher Soat1 expression levels agree with publicly available databases for expression of these genes in astrocytes in the brain (47).”

• cites [47] Zhang, 2014, An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex, J. Neurosci. sourcePartly supported

  The section 'An RNA-Seq transcriptome database of purified cell classes of the brain' establishes that the paper provides astrocyte gene-expression data. Neither that section nor the passages retrieved for Soat1 and Soat2 report their expression levels, so our copy does not verify the claimed agreement for those genes. The supplied passages give no page number for the relevant section. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Expression of APOE is controlled by LXRs in a human astrocytoma cell line (CCF-STTG1), where synthetic LXR agonists as well as oxysterols promote ApoE gene expression.

“Expression of APOE is controled by LXRs (51) in a human astrocytoma cell line (CCF-STTG1), where synthetic LXR agonists as well as oxysterols promote ApoE gene expression (52,53).”

• cites [51] Laffitte, 2001, LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes, Proc. Natl. Acad. Sci. U. S. A. sourceSupported
• cites [52] Liang, 2004, A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes, J. Neurochem. sourceNot checked — no full text of the source
• cites [53] Abildayeva, 2006, 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux, J. Biol. Chem. sourceSupported

May combine two claims.

Overexpression of LDLR reduced ApoE levels and reduced tau-mediated neurodegeneration.

“Overexpression of LDLR reduced ApoE levels and reduced tau-mediated neurodegeneration (63).”

• cites [63] Shi, 2021, Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms, Neuron sourceSupported

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

Increased lipid droplet accumulation in ApoE4-expressing astrocytes has been thought to result from dysregulation of lipid homeostasis in neuroinflammation.

“Increased LD accumulation in ApoE4-expressing astrocytes has been thought to result from the dysregulation of lipid homeostasis in neuroinflammation (20)(21)(22).”

• cites [20] Farmer, 2019, Apolipoprotein E4 alters astrocyte fatty acid metabolism and lipid droplet formation, Cells sourcePartly supported

  The Conclusions (Section 5; page unavailable) report more lipid droplets and altered fatty-acid metabolism in E4 astrocytes than in E3 astrocytes. The paper does not establish that neuroinflammation causes the increased accumulation, so that explanation is not supported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [21] Sienski, 2021, APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia, Sci. Transl. Med. sourcePartly supported

  The Results section reports greater lipid-droplet accumulation and altered lipid composition in APOE4-expressing human iPSC-derived astrocytes than in APOE3 counterparts. It does not establish that this occurs in neuroinflammation; the reported interferon-gamma stimulation involved microglia, not astrocytes. No page numbers are available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [22] Lindner, 2022, Isoform- and cell-state-specific lipidation of ApoE in astrocytes, Cell Rep. sourcePartly supported

  The Introduction and Discussion report that ApoE4-expressing astrocytes accumulate more lipid droplets than ApoE3 astrocytes and describe altered lipid handling. They do not attribute that accumulation to dysregulated lipid homeostasis in neuroinflammation; the Discussion instead discusses aging, stress, and metabolic perturbation. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

A previous study showed that LY295427 reverses the effect of 25HC on the SREBP pathway by elevating the expression of Ldlr as well as Insig1, presumably by creating a sink for 25HC.

“A previous study showed that LY295427 reverses the effect of 25HC on the SREBPpathway by elevating the expression of Ldlr (64) as well as Insig1 (44) presumably by creating a sink for 25HC.”

• cites [64] Bowling, 1996, LY295427, a novel hypocholesterolemic agent, enhances [3H]25-hydroxycholesterol binding to liver cytosolic proteins, J. Lipid Res. sourceNot checked — no full text of the source
• cites [44] Janowski, 2002, The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP, Proc. Natl. Acad. Sci. U. S. A. sourceSupported

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

Unlike triglyceride-enriched lipid droplets, cholesteryl ester-enriched lipid droplets are thought to play an important role in the biosynthesis of steroid hormones.

“Unlike triglyceride-enriched LDs, CE-enriched LDs are thought to play an important role in the biosynthesis of steroid hormones (65).”

• cites [65] Shen, 2016, Lipid droplets and steroidogenic cells, Exp. Cell Res. sourceSupported

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

Storage and utilization of lipids in lipid droplets in astrocytes are important for astrocyte lipid homeostasis and function.

“Storage and utilization of lipids in LDs in astrocytes are important for astrocyte lipid homeostasis and function (48).”

• cites [48] Lee, 2021, Lipid metabolism in astrocytic structure and function, Semin. Cell Dev. Biol. sourceSupported

May combine two claims.

Treatment of astrocytes with 25HC increases extracellular levels of ApoE lipoprotein particles without increasing Apoe mRNA expression.

“Extracellular levels of ApoE lipoprotein particles increased after treatment of astrocytes with 25HC without an increase in Apoe mRNA expression.”

The quote only partly states this claim.

By 24 h, 25HC was clearly present in intracellular vesicles in virtually every astrocyte.

“By 24 h, 25HC was clearly present in intracellular vesicles in virtually every cell.”

• AssumptionRests on an assumption: The fluorescently labeled 25HC (TopFluor-25HC) is a valid tracer for unlabeled 25HC in uptake and localization studies.

May combine two claims.

25HC increases over time in media from WT microglia, but no 25HC is detectable in media from ch25h-/- microglia after LPS challenge.

“Increasing amounts of 25HC as a function of time were observed exclusively in media from WT microglia, whereas no 25HC was detectable in media from ch25h-/-microglia.”

• AssumptionRests on an assumption: 25HC detected in the culture media is secreted by microglia and not released by cell lysis.

May combine two claims.

25HC directly modulates astrocyte lipid metabolism via activation of LXR-mediated and inhibition of SREBP-mediated gene expression and by increasing cholesterol esterification.

“Here, we report that 25HC directly modulates astrocyte lipid metabolism via activation of LXR-mediated and inhibition of SREBP-mediated gene expression as well as by increasing cholesterol esterification.”

May combine two claims.

In microglia, Ch25h expression was low in the absence of LPS and increased about 100-fold to 200-fold after treatment with LPS.

“In microglia, Ch25h was low in the absence of LPS and increased about 100-fold to 200fold after treatment with LPS (Fig. 1A).”

May combine two claims.

Microglia produce high levels of 25HC after LPS treatment, whereas astrocytes produce no appreciable amounts of 25HC with or without LPS.

“While microglia produced high levels of 25HC after LPS treatment, astrocytes produced no appreciable amounts of 25HC with or without LPS (Fig. 1B).”

May combine two claims.

25HC suppresses expression of Srebf2 but not Srebf1, leading to reduced cholesterol synthesis in astrocytes without affecting fatty acid levels.

“25HC also suppressed expression of Srebf2, but not Srebf1, leading to reduced cholesterol synthesis in astrocytes without affecting fatty acid levels.”

May combine two claims.

In astrocytes, Ch25h expression was low in the absence of LPS and increased only marginally upon treatment with LPS.

“In astrocytes, Ch25h was low in the absence of LPS and increased only marginally upon treatment with LPS, presumably resulting from the low levels of contaminating microglia (Fig. 1A).”

May combine two claims.

25HC enhances esterification of cholesterol and the accumulation of lipid droplets in astrocytes.

“In addition, 25HC enhances esterification of cholesterol and the accumulation of LDs in astrocytes.”

May combine two claims.

Astrocytes take up externally added 25HC and respond with altered lipid metabolism.

“Here, we show that astrocytes take up externally added 25HC and respond with altered lipid metabolism.”

May combine two claims.

Apoe expression is neither elevated by 25HC treatment nor inhibited by treatment with the LXR antagonist GSK2033.

“Further, Apoe expression is neither elevated by 25HC treatment nor inhibited by treatment with the LXR antagonist, GSK2033.”

May combine two claims.

25HC had no effect on the expression of Srebf1, while T0901317 increased Srebf1 by about 50%.

“Interestingly, while 25HC had no effect on the expression of Srebf1 (encoding SREBP1, the transcription factor regulating fatty acid synthesis genes), T0901317 increased Srebf1 by about 50% (Fig. 5C).”

May combine two claims.

25HC increased extracellular ApoE but not ApoJ.

“25HC increased extracellular ApoE but not ApoJ suggesting that the effect was specific for ApoE (Fig. 3E).”

May combine two claims.

Abca1 protein levels increased and Ldlr protein levels decreased following 25HC treatment.

“In accordance with the mRNA expression levels Abca1 protein levels increased, while Ldlr protein levels decreased following 25HC treatment (Fig. 4C).”

May combine two claims.

Avasimibe had no effect on lipid droplets induced by oleic acid alone, but eliminated the lipid droplet-stimulatory effect of 25HC and reverted the levels to that of oleic acid alone.

“While avasimibe had no effect on LDs induced by OA alone, it eliminated the LD-stimulatory effect of 25HC and reverted the levels to that of OA alone.”

May combine two claims.

Astrocytes readily take up and accumulate 25HC, suggesting that the intracellular concentrations of 25HC may be relatively high.

“However, we have shown that astrocytes readily take up and accumulate 25HC suggesting that the intracellular concentrations of 25HC may be relatively high.”

May combine two claims.

Ldlr expression was suppressed by 25HC and this suppression was unaffected by GSK2033.

“Expression of Ldlr was suppressed by 25HC as expected and this suppression was unaffected by the presence of GSK2033 (Fig. 4F).”

May combine two claims.

25HC reduced the expression of Insig1 to about 20%, while T0901317 marginally increased Insig1.

“Similarly, while 25HC also reduced the expression of Insig1 (a major regulator of the SREBP pathway) to about 20%, T0901317 marginally increased Insig1 (Fig. 5B).”

May combine two claims.

In the absence of oleic acid, 25HC increased lipid droplet counts in astrocytes and this increase was reversed by avasimibe.

“In the absence of OA, 25HC increased LD counts in astrocytes and this increase was reversed by avasimibe (Fig. 6E, F) suggesting that the increased CEs in 25HC-treated astrocytes were stored in LDs.”

May combine two claims.

25HC did not affect the expression of Fasn, while T0901317 increased Fasn by 250%.

“Likewise, while 25HC did not affect the expression of Fasn, T0901317 increased Fasn by 250% (Fig. 5D).”

May combine two claims.

Basal secreted ApoE in conditioned media was low at 1 day and increased by 4-fold to 5-fold over 2 days.

“At earlier time points (1-day), basal secreted levels of ApoE in conditioned media were low under control conditions and increased by 4-fold to 5-fold over 2 days (Fig. 3B).”

May combine two claims.

Expression of Srebf2 was reduced to 50% following 25HC treatment of astrocytes for 1 day, whereas T0901317 did not affect Srebf2 expression.

“Expression of Srebf2 (encoding SREBP2, the transcription factor regulating sterol synthesis genes) was reduced to 50% following 25HC treatment of astrocytes for 1 day, whereas T0901317 did not affect Srebf2 expression (Fig. 5A).”

May combine two claims.

Vehicle or T0901317 showed no effect on Ldlr expression.

“On the other hand, 25HC strongly suppressed the expression of Ldlr to about 10% of control (P < 0.001), while treatments with vehicle or T0901317 showed no effect on Ldlr expression (Fig. 4B).”

May combine two claims.

25HC had a much weaker influence on extracellular ApoE4; ApoE4 increased marginally at 2 μM and by about 1.4-fold at 4 μM.

“On the other hand, 25HC had a much weaker influence on extracellular ApoE4.Extracellular ApoE4 levels increased marginally at 2 μM 25HC and by about 1.4-fold by 4 μM 25HC.”

May combine two claims.

Neither addition of oleic acid nor inhibition of cholesterol esterification by avasimibe altered basal or 25HC-stimulated levels of extracellular ApoE.

“Neither additional of OA nor inhibition of cholesterol esterification by avasimibe altered basal or 25HC-stimulated levels of extracellular ApoE (Fig. 6H).”

May combine two claims.

High levels of 25HC produced by LPS-treated microglia reflect the high levels of Ch25h expression, demonstrating a causal relationship between Ch25h expression and 25HC production in microglia.

“High levels of 25HC produced by LPS-treated microglia reflected the high levels of Ch25h expression, demonstrating a causal relationship between Ch25h expression and 25HC production in microglia.”

May combine two claims.

Microglial 25HC not only elicits autocrine effects within microglia but may also exert paracrine effects on surrounding cells such as neurons, astrocytes, and other cells to facilitate intercellular crosstalk.

“suggesting that microglial 25HC not only elicit autocrine effects within microglia but may also exert paracrine effects on surrounding cells such as neurons, astrocytes, and other cells to facilitate intercellular crosstalk.”

• AssumptionRests on an assumption: 25HC detected in the culture media is secreted by microglia and not released by cell lysis.

May combine two claims.

25HC exhibits autocrine effects on Ch25h-expressing myeloid cells and paracrine effects on neighboring cells.

“These findings illustrate that 25HC not only exhibits autocrine effects on Ch25h-expressing myeloid cells but also supports paracrine effects on neighboring cells.”

May combine two claims.

Astrocytes expressing APOE4 have impaired lipid metabolism and increased accumulation of lipid droplets relative to APOE3-expressing astrocytes.

“Astrocytes expressing APOE4 have impaired lipid metabolism and increased accumulation of lipid droplets (LDs) relative to APOE3expressing astrocytes (20)(21)(22).”

• cites (20)(21)(22)Not matched

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

May combine two claims.

Inflammatory stimuli trigger overexpression of Ch25h and production of 25HC by microglia but not astrocytes.

“Therefore, we conclude that inflammatory stimuli triggered overexpression of Ch25h and production of 25HC by microglia but not astrocytes.”

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

The expression of Ch25h in primary cultured astrocytes may indicate an altered astrocyte gene expression profile upon isolation and culture.

“However, expression of Ch25h has also been reported in primary cultured astrocytes (36) and may indicate an altered astrocyte gene expression profile upon isolation and culture.”

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

In a mouse model of amyloid deposition, ApoE promotes the localization of astrocytes to plaques.

“In a mouse model of amyloid deposition, ApoE has been reported to promote the localization of astrocytes to plaques (19).”

• cites [19] Koistinaho, 2004, Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides, Nat. Med. sourceNot checked — no full text of the source

May combine two claims.

The increase in extracellular ApoE caused by 25HC is due to elevated efflux from increased Abca1 expression via LXRs and decreased lipoprotein reuptake from suppressed Ldlr expression via inhibition of SREBP.

“Increased extracellular ApoE was due to elevated efflux from increased Abca1 expression via LXRs as well as decreased lipoprotein reuptake from suppressed Ldlr expression via inhibition of SREBP.”

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

25HC has antiviral properties and context-dependent immunomodulatory effects that can be proinflammatory or anti-inflammatory.

“25HC has been shown to have antiviral properties and exhibit context-dependent immunemodulatory effects which can be either proinflammatory or anti-inflammatory (12,13).”

• cites [12] Diczfalusy, 2013, On the formation and possible biological role of 25-hydroxycholesterol, Biochimie sourceNot checked — no full text of the source
• cites [13] Cyster, 2014, 25-Hydroxycholesterols in innate and adaptive immunity, Nat. Rev. Immunol. sourceNot checked — no full text of the source

May combine two claims.

Primary mouse microglia cultures were all Iba1-positive with no detectable GFAP-positive cells, and astrocyte cultures were nearly all GFAP-positive with only about 1% Iba1-positive microglia.

“While all cells in the microglia culture were positive for Iba1 with no detectable GFAP-positive cells, nearly all cells in the astrocyte cultures were GFAP-positive with only about 1% of Iba1-positive microglia.”

May combine two claims.

Activated microglia express higher levels of Ch25h than homeostatic microglia, and Ch25h is overexpressed in myeloid cells in mouse models of neurological disorders.

“Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC).”

• Also stated in: § Abstract · plain

  “Single cell and single nuclei transcriptomics studies show myeloid cell specific overexpression of Ch25h in various mouse models of neurological disorders ((7); http://research-pub.gene.com/ BrainMyeloidLandscape/BrainMyeloidLandscape2/#).”

• cites [7] Friedman, 2018, Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s Disease not evident in mouse models, Cell Rep. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

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

Astrocytes are a major cell type in the brain for cholesterol biosynthesis, which is controlled by Srebf2 and may play an important role in the pathogenesis of AD.

“Astrocytes are a major cell type in the brain for cholesterol biosynthesis, which is controled by Srebf2 (42) and may play an important role in the pathogenesis of AD.”

• cites [42] Brown, 2002, Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism, Mol. Cell sourceNot checked — no full text of the source

May combine two claims.

25HC alters astrocyte lipid metabolism and lipid homeostasis in various ways, including cholesterol metabolism, lipoprotein efflux, reuptake, and lipid droplet accumulation.

“In this study, we have provided evidence that 25HC, a cholesterol metabolite produced almost exclusively by activated microglia alters lipid metabolism in astrocytes (Fig. 7).”

• Also stated in: § DISCUSSION · boosted

  “We have shown that 25HC alters astrocyte lipid homeostasis in various ways including altering cholesterol metabolism, lipoprotein efflux, and reuptake as well as lipid droplet accumulation.”

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

Previous studies have shown that 25HC activates cholesterol esterification by SOAT (also known as ACAT).

“Previous studies have shown that 25HC activates cholesterol esterification by SOAT (also known as ACAT) (46).”

• cites [46] Brown, 1975, Cholesterol ester formation in cultured human fibroblasts. Stimulation by oxygenated sterols, J. Biol. Chem. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

The lower extracellular levels of ApoE4-containing lipoproteins relative to ApoE3-containing lipoproteins in response to 25HC treatment may involve other unknown mechanisms.

“This suggests that the lower extracellular levels of ApoE4-containing lipoproteins relative to ApoE3-containing lipoproteins in response to 25HC treatment may involve other unknown mechanisms.”

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

Quantitation of the 25HC-mediated increase in ApoE3- and ApoE4-containing lipoproteins would be inappropriate due to the immuno-isolation step.

“While the electron micrographs are also suggestive of 25HC-mediated increase in ApoE3-and ApoE4-containing lipoproteins, quantitation of this increase would be inappropriate due to the immuno-isolation step.”

May combine two claims.

The effects of 25HC on astrocytes resulted from upregulation of LXR-mediated gene expression and downregulation of SREBP-mediated gene expression.

“These effects resulted from upregulation of the LXR-mediated gene expression and downregulation of SREBP-mediated gene expression by 25HC.”

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

Polymorphisms in the SREBF2 gene (rs2269657) have been reported to be associated with the risk of developing late onset AD, and SREBF2 mRNA was reported to be significantly higher in AD temporal cortex and cerebellum.

“Polymorphisms in the SREBF2 gene (rs2269657) have been reported to be associated with the risk of developing late onset AD and SREBF2 mRNA was reported to be significantly higher in AD temporal cortex and cerebellum (55).”

• cites [55] Picard, 2018, Alterations in cholesterol metabolism-related genes in sporadic Alzheimer’s disease, Neurobiol. Aging sourceNot checked — no full text of the source

May combine two claims.

Cholesteryl esters produced in response to 25HC treatment of astrocytes were stored in lipid droplets but not in ApoE-containing lipoproteins at basal levels or when cotreated with oleic acid.

“These results suggest that CEs produced in response to treatment of astrocytes with 25HC were stored in LDs but not in ApoE-containing lipoproteins at basal levels as well as when cotreated with an acyl-donor such as OA.”

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

Nuclear Srebp2 has been reported to be negatively correlated with the presence of AT8-positive neurofibrillary tangles in AD brain.

“Further, nuclear Srebp2 has been reported to be negatively correlated with the presence of AT8-positive neurofibrillary tangles in AD brain (57).”

• cites [57] Wang, 2019, The sterol regulatory element-binding protein 2 is dysregulated by tau alterations in Alzheimer disease, Brain Pathol. sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

25HC may function as a potential mediator of microglia-astrocyte crosstalk leading to dysregulation of astrocyte lipid metabolism under conditions of neuroinflammation.

“We postulate that 25HC may function as a potential mediator of microglia-astrocyte crosstalk leading to dysregulation of astrocyte lipid metabolism under conditions of neuroinflammation.”

May combine two claims.

When 25HC binds to Insig1, it stabilizes the protein by reducing proteasomal degradation of Insig1, thus promoting its interaction with Scap-Srebp2.

“When 25HC binds to Insig1, it also stabilizes the protein by reducing proteasomal degradation of Insig1 thus promoting its interaction with Scap-Srebp2 (60).”

• cites [60] Gong, 2006, Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake, Cell Metab. sourceNot checked — no full text of the source

May combine two claims.

With increased cholesterol efflux, increased cholesterol esterification, and decreased cholesterol biosynthesis, the net effect of 25HC on astrocytes is a reduction in overall free cholesterol levels by about 10%.

“With increased cholesterol efflux, increased cholesterol esterification and decreased cholesterol biosynthesis, the net effect of 25HC on astrocytes is a reduction in overall free cholesterol levels by about 10% in astrocytes as we empirically established.”

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

Ldlr is normally localized to the plasma membrane where it binds extracellular ApoE lipoproteins followed by endocytosis and subsequent release of bound lipids in the lysosome.

“Ldlr is normally localized to the plasma membrane where it binds extracellular ApoE lipoproteins followed by endocytosis and subsequent release of bound lipids in the lysosome (62).”

• cites [62] Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science sourceNot checked — no full text of the source

May combine two claims.

Insig1 is a target of the Srebp-signaling pathway, and its expression is reduced in the presence of 25HC.

“Since Insig1 is a target of the Srebp- signaling pathway (60), expression of Insig1 is also reduced in the presence of 25HC.”

• cites [60] Gong, 2006, Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake, Cell Metab. sourceNot checked — no full text of the source

May combine two claims.

Microglial 25HC overproduced under neuroinflammatory conditions may be a potentially important feedback regulator of the SREBP machinery in astrocytes, leading to reduced cholesterol biosynthesis as well as lipoprotein reuptake.

“Taken together, microglial 25HC overproduced under neuroinflammatory conditions may be a potentially important feedback regulator of the SREBP machinery in astrocytes leading to reduced cholesterol biosynthesis as well as lipoprotein reuptake.”

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

Astrocyte-derived cholesterol was reported to be important for beta-amyloid production in neurons.

“Astrocyte-derived cholesterol was reported to be important for beta-amyloid production in neurons (56).”

• cites [56] Wang, 2021, Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol, Proc. Natl. Acad. Sci. U. S. A.Not matched

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