The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis
Open accessAbstract
Inhibiting the E3 ubiquitin ligase Idol in a mouse model of Alzheimer’s-like pathology ameliorates disease severity by promoting clearance of Aβ peptides by microglia.
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Written from the paper’s full text.
TL;DR
Idol, an E3 ubiquitin ligase targeting LDLR for degradation, is a primary physiological regulator of brain LDLR, ApoE, and Aβ metabolism. In APP/PS1 mice, Idol deficiency increased brain LDLR, decreased ApoE and Aβ, reduced amyloid plaque burden, and ameliorated neuroinflammation.
Key findings
- Brain LDLR protein was strikingly increased in Idol−/− mice, with Idol+/− mice showing intermediate levels consistent with a gene dosage effect (P < 0.05); Idol mRNA was abundant in primary microglia and neurons and lower in astrocytes.
- In 7-month-old APP/PS1 mice, Idol deficiency decreased soluble and insoluble Aβ40 and Aβ42 in cortex in both sexes; male APP/PS1;Idol+/− mice also had significant reductions in insoluble and soluble Aβ42 versus APP/PS1;Idol+/+ mice (P < 0.01), and amyloid plaque burden was reduced in cortex and hippocampus.
- Neuroinflammation was decreased in APP/PS1;Idol−/− versus APP/PS1;Idol+/+ mice by CD45 staining (P < 0.01), and fewer microglia were present in cortex and hippocampus in both heterozygous and homozygous Idol knockout mice (P < 0.01).
- Idol knockdown (~60%) increased LDLR protein and Aβ uptake in Neuro2a, hApoE3, and BV2 cells, decreased Aβ remaining in media after 24 hours, and increased uptake of aggregated Aβ42 and ApoE-containing HDL particles in primary microglia; LDLR knockdown largely abolished the effect of Idol deficiency on Aβ uptake.
Methods
- Idol was genetically ablated in the APPswe/PSEN1dE9 (APP/PS1) mouse model of Aβ amyloidosis; Idol−/− mice were backcrossed to C57BL/6 for eight generations before mating to APP/PS1 mice, and brains were analyzed at 7 months of age with both sexes analyzed independently.
- Outcomes were assessed by ELISA for Aβ40/Aβ42, immunoblotting, quantitative PCR, immunohistochemistry for 82E1, thioflavin S, CD45, and Iba1, and Aβ/ApoE-HDL uptake assays in primary microglia, primary neurons, and cell lines using siRNA, lentiviral Cre, or AAV Cre.
- P values were calculated by Student’s t test; mouse sample collection and all data analysis were performed blinded, while cell culture data collection was performed with investigators aware of sample identities.
Limitations
- The paper states that the relative importance of the three Idol targets for ApoE and Aβ clearance in vivo—LDLR, ApoER2, and VLDLR—has not been tested directly, so contributions of ApoER2 and VLDLR cannot be excluded.
- The paper states that a mouse model was used to study AD-related pathology, and although the LXR-IDOL-LDLR pathway is highly active in primates, further studies are needed to translate the findings to humans.
- Evident from the text: no cognitive or behavioral outcomes are reported, and the mechanistic links between ApoE and Aβ uptake are described as complex and still controversial.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
17 of 29 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Reducing ApoE in mouse models of amyloidosis greatly reduces plaque formation.
“Reducing ApoE in mouse models of amyloidosis greatly reduces plaque formation (7, 8, 33, 34).”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [7] Bien-Ly N, Gillespie AK, Walker D, Yoon SY, Huang Y, Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J. Neurosci 32, 4803– 4811 (2012). 22492035 PMC3433173 source
- cites [8] Kim J, Jiang H, Park S, Eltorai AEM, Stewart FR, Yoon H, Basak JM, Finn MB, Holtzman DM, Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-b amyloidosis. J. Neurosci 31, 18007– 18012 (2011). 22159114 PMC3257514 source
- cites [33] Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ, Piccardo P, Ghetti B, Paul SM, Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat. Genet 17, 263– 264 (1997). 9354781 source
- cites [34] Irizarry MC, Rebeck GW, Cheung B, Bales K, Paul SM, Holzman D, Hyman BT, Modulation of Aβ deposition in APP transgenic mice by an apolipoprotein E null background. Ann. N. Y. Acad. Sci 920, 171– 178 (2000). 11193147 source
- Premisecitation
Loss of Idol expression in mice has little effect on hepatic LDLR.
“By contrast, loss of Idol expression in mice has little effect on hepatic LDLR (13).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] Hong C, Marshall SM, McDaniel AL, Graham M, Layne JD, Cai L, Scotti E, Boyadjian R, Kim J, Chamberlain BT, Tangirala RK, Jung ME, Fong L, Lee R, Young SG, Temel RE, Tontonoz P, The LXR–Idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metab. 20, 910– 918 (2014). 25440061 PMC4261644 source
- Premisecitation
ApoE is a crucial factor in development of AD.
“ApoE is also a crucial factor in the development of AD (5, 6, 31, 32).”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [5] Mahley RW, Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science 240, 622– 630 (1988). 3283935 source
- cites [6] Kim J, Basak JM, Holtzman DM, The role of apolipoprotein E in Alzheimer’s disease. Neuron 63, 287– 303 (2009). 19679070 PMC3044446 source
- cites [31] Kanekiyo T, Xu H, Bu G, ApoE and Aβ in Alzheimer’s disease: Accidental encounters or partners? Neuron 81, 740– 754 (2014). 24559670 PMC3983361 source
- cites [32] Liu C-C, Kanekiyo T, Xu H, Bu G, Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat. Rev. Neurol 9, 106– 118 (2013). 23296339 PMC3726719 source
- Premisecitation
LXR-IDOL-LDLR pathway is highly active in primates.
“We previously reported that the LXR-IDOL-LDLR pathway is highly active in primates (13), but further studies will be needed to translate the current findings to humans.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Hong C, Marshall SM, McDaniel AL, Graham M, Layne JD, Cai L, Scotti E, Boyadjian R, Kim J, Chamberlain BT, Tangirala RK, Jung ME, Fong L, Lee R, Young SG, Temel RE, Tontonoz P, The LXR–Idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metab. 20, 910– 918 (2014). 25440061 PMC4261644 source
- Premisecitation
Loss of LXRα and LXRβ does not lead to complete loss of Idol expression.
“However, it is important to keep in mind that loss of LXRα and LXRβ does not lead to complete loss of Idol expression (15).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Zelcer N, Hong C, Boyadjian R, Tontonoz P, LXR regulates cholesterol uptake through idol-dependent ubiquitination of the LDL receptor. Science 325, 100– 104 (2009). 19520913 PMC2777523 source
- Premisecitation
Loss of LXRα or LXRβ increases Aβ plaque burden in APP/PS1 mouse.
“We previously reported that loss of LXRα or LXRβ increases Aβ plaque burden in the APP/PS1 mouse (50).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [50] Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P, Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver X receptors. Proc. Natl. Acad. Sci. U.S.A 104, 10601– 10606 (2007). 17563384 PMC1890560 source
- Findingown data
LXR agonist treatment does not change ApoE mRNA expression in primary mouse microglia.
“Genes encoding the canonical LXR targets Abca1, Srebp-1c, and Scd-1 were up-regulated in parallel, whereas ApoE mRNA expression was unchanged (Fig. 1C).”
Quote in the paperNot a substantial claim - Findingown data
Fewer microglia are present in brains of APP/PS1;Idol−/− compared to APP/PS1;Idol+/+ mice.
“Furthermore, fewer microglia were present in the brains of APP/PS1;Idol−/− compared to APP/PS1;Idol+/+ mice (Fig. 4, C and D).”
Quote in the paperSubstantial claim - Findingown data
Idol knockdown decreases amount of Aβ remaining in media after 24 hours of incubation.
“Furthermore, Idol knockdown also decreased the amount of Aβ remaining in the media after 24 hours of incubation (Fig. 6C).”
Quote in the paperSubstantial claim - Findingown data
Male and female APP/PS1 mice lacking Idol have reduced thioflavin S-positive plaque burden in cortex and hippocampus.
“Consistent with the Aβ staining results, male and female APP/PS1 mice lacking Idol also had reduced thioflavin S–positive plaque burden in the cortex and hippocampus.”
Quote in the paperSubstantial claim - Findingown data
siRNA-mediated Idol knockdown increases LDLR protein in Neuro2a, hApoE3, and BV2 cells.
“Small interfering RNA (siRNA)–mediated knockdown decreased Idol expression by ~60% and increased LDLR protein in mouse Neuro2a neuronal cells, hApoE3 knock-in astroglial cells, and BV2 microglial cells (Fig. 6A and fig. S3A).”
Quote in the paperSubstantial claim - Findingown data
There is no difference in ability of Idolflox/flox control and Cre-infected Idol-deficient primary mouse neurons to internalize fluorescently labeled aggregated Aβ42 peptide.
“In contrast to the results obtained with the immortalized Neuro2a line, there was no difference in the ability of Idolflox/flox control and Cre-infected Idol-deficient neurons to internalize fluorescently labeled aggregated Aβ42 peptide (Fig. 6D).”
Quote in the paperSubstantial claim - Findingown data
Idol-deficient cells show increased uptake activity toward ApoE-containing lipoproteins.
“We observed a similar increased uptake activity of Idol-deficient cells toward ApoE-containing lipoproteins.”
Quote in the paperSubstantial claim - Findingown data
Incubation of primary microglia with fluorescently labeled reconstituted discoidal HDL particles containing ApoE reveals accelerated uptake in cells lacking Idol.
“Incubation of primary microglia with fluorescently labeled reconstituted discoidal high-density lipoprotein (HDL) particles containing ApoE revealed accelerated uptake in cells lacking Idol (Fig. 7, B and D).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Idol decreases LDLR in Neuro2a mouse neuronal cells.
“We also found that overexpression of Idol decreased LDLR and triggered LDLR ubiquitination in Neuro2a mouse neuronal cells (fig. S1, B to D).”
Quote in the paperSubstantial claim - Findingown data
Idol knockdown strongly increases Aβ uptake in Neuro2a, hApoE3, and BV2 cells.
“We found that Idol knockdown strongly increased Aβ uptake in Neuro2a, hApoE3, and BV2 cells (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
Insoluble and soluble Aβ40 and Aβ42 are prominently decreased in cortex in both male and female APP/PS1;Idol−/− mice compared to APP/PS1;Idol+/+ mice.
“Compared to APP/PS1;Idol+/+ mice, insoluble and soluble Aβ40 and Aβ42 were prominently decreased in the cortex in both male and female APP/PS1;Idol−/− mice (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data
Idolflox/flox primary microglia treated with lentiviral Cre accumulate more Aβ42 peptide upon incubation compared to vector-treated cells.
“Idolflox/flox primary microglia treated with lentiviral Cre accumulated more Aβ42 peptide upon incubation compared to vector-treated cells.”
Quote in the paperSubstantial claim - Findingown data
Primary microglia from Idol−/− mice exhibit increased LDLR expression compared to wild-type microglia.
“Conversely, primary microglia from Idol−/− mice exhibited increased LDLR expression compared to wild-type microglia (Fig. 1E).”
Quote in the paperSubstantial claim - Findingown data
β-Gal protein coexpresses with Iba1 and NeuN in Idol+/− cells.
“Immunohistochemistry confirmed coexpression of β-galactosidase (β-Gal) protein with the microglia marker Iba1 and the neuronal marker NeuN in Idol+/− cells (Fig. 1B).”
Quote in the paperNot a substantial claim - Findingown data
Aβ peptide in RIPA fraction and total brain lysates is markedly reduced in APP/PS1;Idol−/− mice.
“We also assessed Aβ peptide in the RIPA fraction and total brain lysates and found markedly reduced Aβ peptide in APP/PS1;Idol−/− mice (Fig. 2, B and C).”
Quote in the paperSubstantial claim - Findingown data
Induction of Idol by LXR agonist results in marked reduction of LDLR protein in microglia.
“Induction of Idol by an LXR agonist, in turn, resulted in a marked reduction of LDLR protein, consistent with its degradation (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
siRNA-mediated knockdown decreases Idol expression by ~60% in mouse Neuro2a neuronal cells, hApoE3 knock-in astroglial cells, and BV2 microglial cells.
“Small interfering RNA (siRNA)–mediated knockdown decreased Idol expression by ~60% and increased LDLR protein in mouse Neuro2a neuronal cells, hApoE3 knock-in astroglial cells, and BV2 microglial cells (Fig. 6A and fig. S3A).”
Quote in the paperSubstantial claim - Findingown data
Immunoblotting reveals striking increases in LDLR in brains of Idol−/− mice.
“Immunoblotting revealed striking increases in LDLR in the brains of Idol−/− mice (Fig. 1F).”
Quote in the paperSubstantial claim - Findingown data
Loss of Idol does not change expression of signature microglial markers Cd45, Cd68, and Ym1.
“Loss of Idol did not change the expression of the signature microglial markers Cd45, Cd68, and Ym1 (fig. S2A).”
Quote in the paperSubstantial claim - Findingown data
Lower levels of ApoE are observed in PBS-soluble fractions and RIPA fractions of brain lysates from APP/PS1;Idol−/− mice.
“We also observed lower levels of ApoE in phosphate-buffered saline (PBS)–soluble fractions and RIPA fractions of brain lysates from APP/PS1;Idol−/− mice (Fig. 5, B and C).”
Quote in the paperSubstantial claim - Findingown data
Microglial abundance in APP/PS1 brains is directly proportional to Idol gene dosage.
“Microglial abundance in APP/PS1 brains was directly proportional to the Idol gene dosage.”
Quote in the paperSubstantial claim - Findingown data
LRP1 protein is unchanged in APP/PS1;Idol−/− mice.
“LDLR protein expression in APP/PS1 mice was higher in the absence of Idol, whereas LRP1 protein was unchanged (Fig. 5A).”
Quote in the paperNot a substantial claim - Findingown data
LXR agonist does not change Lrp1 protein in microglia.
“Abca1 protein was increased by LXR agonist in microglia as expected, but Lrp1 did not change.”
Quote in the paperNot a substantial claim - Findingown data
Idol deficiency does not affect activation of microglia upon LPS stimulation, as induction of Tnfa, Il1b, Icam1, and Socs3 is not altered.
“Furthermore, Idol deficiency did not affect the activation of microglia upon lipopolysaccharide (LPS) stimulation, as the induction of genes such as Tnfa, Il1b, Icam1, and Socs3 was not altered (fig. S2B).”
Quote in the paperSubstantial claim - Findingown data
LDLR protein expression in APP/PS1 mice is higher in absence of Idol.
“LDLR protein expression in APP/PS1 mice was higher in the absence of Idol, whereas LRP1 protein was unchanged (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
Neuroinflammation as assessed by CD45 staining is clearly decreased in APP/PS1;Idol−/− compared to APP/PS1;Idol+/+ mice (P < 0.01).
“Consistent with the decreased Aβ plaque formation, neuroinflammation (as assessed by CD45 staining) was clearly decreased in APP/PS1;Idol−/− compared to APP/PS1;Idol+/+ mice (Fig. 4, A and B; P < 0.01).”
Quote in the paperSubstantial claim - Findingown data
LXR agonist treatment robustly increases Idol mRNA in primary mouse microglia.
“Treatment with an LXR agonist robustly increased Idol mRNA in primary mouse microglia (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
Both heterozygous and homozygous Idol knockout mice show a decrease in number of microglia in cortex and hippocampus (P < 0.01).
“Both heterozygous and homozygous knockout mice showed a decrease in the number of microglia in the cortex and hippocampus (Fig. 4, C and D; P < 0.01).”
Quote in the paperSubstantial claim - Findingown data
ApoE protein is reduced in APP/PS1;Idol−/− mice compared to APP/PS1;Idol+/+ mice.
“ApoE protein was correspondingly reduced in APP/PS1;Idol−/− mice compared to APP/PS1;Idol+/+ mice (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
Amyloid plaque burden is reduced in cortex and hippocampus in both male and female APP/PS1;Idol−/− mice.
“Consistent with the reduction of Aβ in the setting of Idol deficiency, amyloid plaque burden was reduced in the cortex and hippocampus in both males and females.”
Quote in the paperSubstantial claim - Findingown data
Microglia lacking Idol show increased ability to internalize fluorescently labeled aggregated Aβ42 peptide.
“Microglia lacking Idol showed increased ability to internalize fluorescently labeled aggregated Aβ42 peptide (Fig. 7, A and C).”
Quote in the paperSubstantial claim - Findingown data
Idol mRNA is readily detected in all examined subregions of the mouse central nervous system (CNS).
“Idol mRNA was readily detected in all examined subregions of the mouse central nervous system (CNS) (fig. S1A).”
Quote in the paperNot a substantial claim - Findingown data
LDLR knockdown largely abolishes effect of Idol deficiency on Aβ uptake.
“LDLR knockdown largely abolished the effect of Idol deficiency on Aβ uptake.”
Quote in the paperSubstantial claim - Findingown data
There is a parallel reduction in ApoE protein in insoluble fractions from APP/PS1;Idol−/− mouse brains (P < 0.05).
“In line with our findings of reduced Aβ peptide in the insoluble fraction (Fig. 2A), there was a parallel reduction in ApoE protein in the insoluble fractions from APP/PS1;Idol−/− mouse brains (Fig. 5D; P < 0.05).”
Quote in the paperSubstantial claim - Findingown data
Reduction in insoluble and soluble Aβ42 in cortex of male APP/PS1;Idol+/− mice is significant versus APP/PS1;Idol+/+ mice (P < 0.01).
“The reduction in insoluble and soluble Aβ42 in the cortex of male APP/PS1;Idol+/− mice was also significant versus APP/PS1;Idol+/+ mice (P < 0.01), suggesting that even partial inhibition of Idol activity was sufficient to suppress the accumulation of amyloid plaque.”
Quote in the paperSubstantial claim - Findingown data
Cortical plaque burden in male APP/PS1;Idol+/− mice trends lower compared to male APP/PS1;Idol+/+ mice (P = 0.066).
“In this cohort, the cortical plaque burden in male APP/PS1;Idol+/− mice also trended lower compared to male APP/PS1;Idol+/+ mice (P = 0.066).”
Quote in the paperNot a substantial claim - Findingown data
Overexpression of Idol triggers LDLR ubiquitination in Neuro2a mouse neuronal cells.
“We also found that overexpression of Idol decreased LDLR and triggered LDLR ubiquitination in Neuro2a mouse neuronal cells (fig. S1, B to D).”
Quote in the paperSubstantial claim - Interpretationown data
LXR-Idol pathway is a previously unrecognized determinant of brain LDLR and ApoE and development of AD-like pathology.
“These results identify the LXR-Idol pathway as a previously unrecognized determinant of brain LDLR and ApoE and the development of AD-like pathology.”
Quote in the paperSubstantial claim - Interpretationown data
Idol regulates Aβ uptake in microglia, at least in part, by modulating LDLR levels.
“These data demonstrate that Idol regulates Aβ uptake in microglia, at least in part, by modulating LDLR levels, and strongly suggest that this mechanism contributes to the effects of Idol on Aβ deposition in APP/PS1 mice.”
Quote in the paperSubstantial claim - Interpretationown data
Idol does not directly modulate neuroinflammatory responses.
“Mechanistic studies revealed that Idol does not directly modulate neuroinflammatory responses.”
Quote in the paperSubstantial claim - Interpretationown data
Difference in microglia abundance in APP/PS1 mice in presence and absence of Idol is secondary to difference in Aβ plaque load.
“These data suggest that the difference in microglia abundance in APP/PS1 mice in the presence and absence of Idol is secondary to the difference in Aβ plaque load.”
Quote in the paperSubstantial claim - Interpretationown data
Idol regulates uptake and clearance of ApoE and Aβ by microglia.
“Rather, Idol regulates the uptake and clearance of ApoE and Aβ by microglia.”
Quote in the paperSubstantial claim - Interpretationown data
Even partial inhibition of Idol activity is sufficient to suppress accumulation of amyloid plaque.
“The reduction in insoluble and soluble Aβ42 in the cortex of male APP/PS1;Idol+/− mice was also significant versus APP/PS1;Idol+/+ mice (P < 0.01), suggesting that even partial inhibition of Idol activity was sufficient to suppress the accumulation of amyloid plaque.”
Quote in the paperSubstantial claim - Interpretationown data
This mechanism contributes to effects of Idol on Aβ deposition in APP/PS1 mice.
“These data demonstrate that Idol regulates Aβ uptake in microglia, at least in part, by modulating LDLR levels, and strongly suggest that this mechanism contributes to the effects of Idol on Aβ deposition in APP/PS1 mice.”
Quote in the paperSubstantial claim - Interpretationown data
Greater reduction of ApoE in PBS fraction is consistent with extracellular ApoE being the target of Idol and LDLR.
“The greater reduction observed in the PBS fraction is consistent with extracellular ApoE being the target of Idol and LDLR.”
Quote in the paperSubstantial claim - Interpretationown data
Idol expression affects amyloid plaque burden in a gene dosage-dependent manner in a mouse model of AD.
“Overall, these results show that Idol expression affects amyloid plaque burden in a gene dosage–dependent manner in a mouse model of AD.”
Quote in the paperSubstantial claim - Interpretationown data
Idol plays a dominant role in determining LDLR expression in the brain under physiological conditions.
“These observations suggest that Idol plays a dominant role in determining LDLR expression in the brain under physiological conditions.”
Quote in the paperSubstantial claim - Interpretationown data
Even partial Idol inhibition could prove beneficial in setting of AD.
“The observation that loss of only one copy of the Idol gene affects Aβ-dependent pathology in mice suggests that even partial Idol inhibition could prove beneficial in the setting of AD.”
Quote in the paperSubstantial claim
- May combine two claims. 11
- Classified as probably not a substantial claim. 9
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationDeletion of Pcsk9 in mice leads to increased LDLR protein in liver but not in brain.
“Deletion of Pcsk9 in mice leads to increased LDLR protein in the liver but not in the brain (41, 42).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [41] Liu M, Wu G, Baysarowich J, Kavana M, Addona GH, Bierilo KK, Mudgett JS, Pavlovic G, Sitlani A, Renger JJ, Hubbard BK, Fisher TS, Zerbinatti CV, PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain. J. Lipid Res 51, 2611– 2618 (2010). 20453200 PMC2918444 source
- cites [42] Rousselet E, Marcinkiewicz J, Kriz J, Zhou A, Hatten ME, Prat A, Seidah NG, PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke. J. Lipid Res 52, 1383– 1391 (2011). 21518694 PMC3111744 source
The Introduction says Pcsk9 disruption prevents LDLR degradation, and Fig. 1 compares LDLR protein in the livers of wild-type and knockout mice. The Discussion reports unchanged LDLR in the adult brain areas examined, but approximately 2.5-fold higher levels in developing knockout brains and a smaller LDLR decrease after ischemic stroke. The unqualified claim that brain LDLR does not increase omits those exceptions (page unavailable in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationInactivation of Ldlr or Lrp1 increases, whereas overexpression of LDLR decreases, ApoE protein in the brain.
“Inactivation of the Ldlr or Lrp1 gene increases, whereas overexpression of LDLR decreases, ApoE protein in the brain (19, 35–37).”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [19] Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM, Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular Aβ clearance. Neuron 64, 632– 644 (2009). 20005821 PMC2787195 source
The Discussion reports that LDLR deficiency increased brain apoE levels by about 50%, and the Results show that LDLR overexpression decreased apoE protein in mouse cortex and hippocampus. The paper also discusses LRP1 as an apoE receptor, but the passages found do not state that inactivation of the Lrp1 gene increases brain apoE protein. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [35] Cao D, Fukuchi K, Wan H, Kim H, Li L, Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice. Neurobiol. Aging 27, 1632– 1643 (2006). 16236385 source
- cites [36] Fryer JD, DeMattos RB, McCormick LM, O’Dell MA, Spinner ML, Bales KR, Paul SM, Sullivan PM, Parsadanian M, Bu G, Holtzman DM, The low density lipoprotein receptor regulates the level of central nervous system human and murine Apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. J. Biol. Chem 280, 25754– 25759 (2005). 15888448 source
The Results (page not provided) report that Ldlr knockout increased apoE in mouse CSF and cortical tissue. The paper does not establish that Lrp1 inactivation increases brain apoE; the Discussion says its effect was difficult to assess. LDLR overexpression increased apoE uptake and degradation in cultured cells, but the paper does not report that it decreased brain apoE protein. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [37] Liu Q, Zerbinatti CV, Zhang J, Hoe H-S, Wang B, Cole SL, Herz J, Muglia L, Bu G, Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56, 66– 78 (2007). 17920016 PMC2045076 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLXRα and LXRβ control expression of an array of genes important for cholesterol metabolism, which may exert independent effects on development of amyloidosis and neuroinflammation.
“Furthermore, LXRα and LXRβ control the expression of an array of genes important for cholesterol metabolism, which may exert independent effects on the development of amyloidosis and neuroinflammation (51).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [51] Zelcer N, Tontonoz P, Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Invest 116, 607– 614 (2006). 16511593 PMC1386115 source
Figure 1 describes LXRs as transcription factors that induce cholesterol-related target genes, and the section ‘LXRs as regulators of macrophage inflammatory signaling’ reports anti-inflammatory activity for both isoforms. The cited paper does not address amyloidosis or neuroinflammation, so it does not support the proposed effects on those conditions. The available passages have no page numbers. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLXR agonist treatment alleviates AD-like pathology in mouse models of amyloidosis, possibly by inducing Abca1 expression.
“LXR agonist treatment alleviates AD-like pathology in mouse models of amyloidosis, possibly by inducing Abca1 expression (29, 43–48).”
Quote in the paperNot a substantial claim2 of 7 sources checked- cites [29] Jiang Q, Lee CYD, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE, ApoE promotes the proteolytic degradation of Aβ. Neuron 58, 681– 693 (2008). 18549781 PMC2493297 source
- cites [43] Burns MP, Vardanian L, Pajoohesh-Ganji A, Wang L, Cooper M, Harris DC, Duff K, Rebeck GW, The effects of ABCA1 on cholesterol efflux and Aβ levels in vitro and in vivo. J. Neurochem 98, 792– 800 (2006). 16771834 source
- cites [44] Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL, ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J. Biol. Chem 285, 34144– 34154 (2010). 20739291 PMC2962513 source
- cites [45] Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS, The liver X receptor ligand T0901317 decreases amyloid b production in vitro and in a mouse model of Alzheimer’s disease. J. Biol. Chem 280, 4079– 4088 (2005). 15557325 source
The In Vivo LXR Ligand Treatment section reports increased brain ABCA1 expression and significantly decreased soluble Aβ40 and Aβ42 after T0901317 treatment in young APP23 mice. The Discussion proposes ABCA1 as a possible mediator. The study supports reduced amyloidogenic processing in one mouse model, but does not show that established AD-like pathology was alleviated. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [46] Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R, Expression profiling in APP23 mouse brain: Inhibition of Aβ amyloidosis and inflammation in response to LXR agonist treatment. Mol. Neurodegener 2, 20 (2007). 17953774 PMC2214725 source
- cites [47] Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK, Ring RH, Kirksey Y, Aschmies S, Xu J, Kubek K, Hirst WD, Gonzales C, Chen Y, Murphy E, Leonard S, Vasylyev D, Oganesian A, Martone RL, Pangalos MN, Reinhart PH, Jacobsen JS, The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease, Mol. Cell. Neurosci 34, 621– 628 (2007). 17336088 source
- cites [48] Vanmierlo T, Rutten K, Dederen J, Bloks VW, van LC Vark-van der Zee, F. Kuipers, A. Kiliaan, A. Blokland, E. J. G. Sijbrands, H. Steinbusch, J. Prickaerts, D. Lütjohann, M. Mulder, Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiol. Aging 32, 1262– 1272 (2011). 19674815 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies suggested Idol inhibition may have beneficial effects on plasma LDL in primates.
“Previous studies have suggested that Idol inhibition may have beneficial effects on plasma LDL in primates (13).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Hong C, Marshall SM, McDaniel AL, Graham M, Layne JD, Cai L, Scotti E, Boyadjian R, Kim J, Chamberlain BT, Tangirala RK, Jung ME, Fong L, Lee R, Young SG, Temel RE, Tontonoz P, The LXR–Idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metab. 20, 910– 918 (2014). 25440061 PMC4261644 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAbca1 affects lipidation status of ApoE in the brain.
“Abca1 affects the lipidation status of ApoE in the brain (49), which, in turn, may facilitate the proteolytic degradation of Aβ (29).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM, ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J. Biol. Chem 279, 40987– 40993 (2004). 15269217 source
May combine two claims.
Findingown dataIdol genotype does not affect total APP protein, BACE1 expression, or β-CTF expression.
“Idol genotype did not affect total APP protein, nor did it affect the expression of the cleavage enzyme BACE1 or its cleavage product β C-terminal fragment (β-CTF).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLDLR protein amount in Idol+/− mice is intermediate between wild-type and Idol−/− mice, consistent with a gene dosage effect (P < 0.05).
“The amount of LDLR protein in Idol+/− mice was intermediate between the amounts of LDLR protein in wild-type and Idol−/− mice, consistent with a gene dosage effect (P < 0.05; Fig. 1F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIdol mRNA is abundant in primary mouse microglia and neurons and lower in astrocytes.
“Analysis of different cell types present in the CNS revealed abundant Idol mRNA in primary mouse microglia and neurons and lower amounts in astrocytes (Fig. 1A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLXR agonist treatment up-regulates Abca1, Srebp-1c, and Scd-1 genes in primary mouse microglia.
“Genes encoding the canonical LXR targets Abca1, Srebp-1c, and Scd-1 were up-regulated in parallel, whereas ApoE mRNA expression was unchanged (Fig. 1C).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataLXR agonist increases Abca1 protein in microglia.
“Abca1 protein was increased by LXR agonist in microglia as expected, but Lrp1 did not change.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIdol affects amyloid plaque formation by modulating LDLR protein primarily in microglia and, consequently, ApoE protein in the brain.
“Our data suggest that Idol affects amyloid plaque formation by modulating LDLR protein primarily in microglia and, consequently, ApoE protein in the brain.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataLoss of Idol decreases Aβ deposition in the brain by enhancing clearance of both Aβ- and ApoE-containing lipoproteins, primarily by microglia.
“Together, these data suggest that loss of Idol decreases Aβ deposition in the brain by enhancing the clearance of both Aβ- and ApoE-containing lipoproteins, primarily by microglia.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE plays a central role in brain lipid homeostasis by mediating endocytosis of HDL-like lipoprotein particles.
“ApoE plays a central role in brain lipid homeostasis by mediating the endocytosis of HDL-like lipoprotein particles (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH, Lipoproteins and their receptors in the central nervous system. characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain. J. Biol. Chem 262, 14352– 14360 (1987). 3115992 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenData collection from mouse samples and all data analysis in both tissue culture and mouse experiments were performed in a blinded fashion.
“Data collection from mouse samples and all the data analysis in both tissue culture and mouse experiments were performed in a blinded fashion.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Study design and conductnone givenAll experiments in this study were performed in duplicate or triplicate.
“All experiments were performed in duplicate or triplicate.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenData were collected from cell culture studies with investigators aware of sample identities.
“Data were collected from cell culture studies with the investigators aware of the sample identities.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The question of whether increasing endogenous LDLR expression would affect AD pathogenesis remains to be addressed.
“However, the question of whether increasing endogenous LDLR expression would affect AD pathogenesis remains to be addressed.”
The paper relies on this without support.
Aβ deposition at 7 months of age is a time when early amyloidosis is apparent.
“The extent of Aβ deposition in the brains of the progeny was analyzed at 7 months of age, a time when early amyloidosis is apparent.”
The paper relies on this without support.
ApoE binds to lipoprotein receptors such as LDLR and LRP1.
“ApoE binds to lipoprotein receptors such as LDLR and LRP1.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Idol is expressed ubiquitously, with the highest expression in microglia and neurons in the brain.
“Idol is expressed ubiquitously, with the highest expression in microglia and neurons in the brain. 20 , 49”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
The Results section on the LXR-Idol pathway reports Idol mRNA in all examined mouse CNS subregions, with abundant expression in microglia and neurons and lower expression in astrocytes. This supports the brain-cell comparison, but not an unqualified claim that Idol is expressed ubiquitously beyond the examined CNS regions. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPrior studies showed that the IDOL pathway in the CNS affects the function of both microglia and neurons.
“Prior studies showed that the IDOL pathway in the CNS affects the function of both microglia and neurons29,30”
From IDOL regulates systemic energy balance through control of neuronal VLDLR expression (2019) · cites this paper as [29]
The Results section, “Loss of Idol facilitates ApoE and Aβ uptake and clearance” (page unavailable), shows that Idol regulates Aβ uptake in primary microglia and that Idol knockdown increases uptake in a neuronal cell line. It also reports no change in Aβ uptake in primary mouse neurons lacking Idol, so the broad claim about neuronal function needs that qualification. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIDOL deficiency resulted in a significant reduction of apoE levels, induction of Aβ clearance, decrease of amyloid plaque burden, and amelioration of neuroinflammation in APP/PS1 mice.
“IDOL deficiency resulted in a significant reduction of apoE levels, induction of Aβ clearance, decrease of amyloid plaque burden, and amelioration of neuroinflammation in APP/PS1 mice”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Choi et al 2015
The Results sections on amyloid burden, neuroinflammation, and ApoE report lower brain ApoE and Aβ levels, reduced plaques, and decreased neuroinflammation in APP/PS1 mice lacking Idol (pages not provided). The section on ApoE and Aβ uptake and clearance shows increased Aβ uptake in cultured cells, but only suggests enhanced clearance as the mechanism in the mice; it does not directly establish induced Aβ clearance in vivo. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTargeting IDOL is an effective way to reduce apoE brain levels.
“targeting IDOL is an effective way to reduce apoE brain levels (Choi et al 2015, Gao et al 2020)”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Choi et al 2015
The Results report lower brain ApoE in APP/PS1 mice lacking Idol, supporting the claim for genetic deletion in this mouse model. The Discussion says pharmacological Idol inhibition merits further investigation and that translation to humans requires more study; it does not establish targeting IDOL as an effective intervention generally. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPrior work using conventional global Idol knockout demonstrated that Idol deletion increases endogenous LDLR levels, coinciding with reduced amyloid plaque burden and neuroinflammation in an Aβ-amyloidosis mouse model.
“Our prior work using a conventional global Idol knockout (KO) model demonstrated that Idol deletion was sufficient to increase endogenous LDLR levels, coinciding with reduced amyloid plaque burden and neuroinflammation in an Aβ‐amyloidosis mouse model. 20”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
Idol is expressed predominantly in microglia and neurons in the brain.
“Because Idol is expressed predominantly in microglia and neurons in the brain, 20 we generated microglia‐ and neuron‐specific Idol KO mouse models”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
Constitutive deletion of Idol ameliorated Aβ-amyloidosis pathology.
“We previously demonstrated that constitutive deletion of the Idol gene ameliorated Aβ‐amyloidosis pathology. 20”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
Idol knockdown increases Aβ uptake in microglia in vitro.
“Previously demonstrated that Idol knockdown increased Aβ uptake in microglia in vitro. 20”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
IDOL may regulate microglial Aβ clearance.
“While IDOL may regulate microglial Aβ clearance, its ubiquitous expression implies that additional mechanisms may contribute to the amyloid reduction observed in Idol constitutive KO mice. 20”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
LDLR mediates the impact of Idol inhibition on microglial Aβ uptake.
“This effect was abolished with Ldlr knockdown, 20 suggesting that LDLR mediates the impact of Idol inhibition on microglial Aβ uptake.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
Previous work using a whole-body Idol KO mouse model demonstrated an increase in brain LDLR levels with a significant decrease in Aβ accumulation.
“Indeed, our previous work using a whole‐body Idol KO mouse model demonstrated an increase in brain LDLR levels with a significant decrease in Aβ accumulation. 20”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
Increasing LDLR levels, either through Ldlr overexpression or by deleting its E3 ubiquitin ligase Idol, reduced APOE levels and attenuated amyloid pathology.
“Notably, increasing LDLR levels, either through Ldlr overexpression or by deleting its E3 ubiquitin ligase Idol, reduced APOE levels and attenuated amyloid pathology.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [20]
Deletion of an E3 ubiquitin ligase increased LDLR and decreased ApoE and amyloid β in the brain.
“Deletion of an E3 ubiquitin ligase increased LDLR and decreased ApoE and amyloid β in the brain.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [19]
IDOL is an E3 ubiquitin ligase that acts as a negative regulator of LDLR in microglia.
“We previously identified E3 ubiquitin ligase IDOL as a negative regulator of LDLR in microglia.”
From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [9]
Ablation of IDOL in both male and female APP/PS1 mice led to decreased soluble and insoluble Aβ, reduced amyloid plaque burden, and ameliorated neuroinflammation.
“Ablation of IDOL in both male and female APP/PS1 mice-a transgenic mouse model of A 𝛃 amyloidosis-led to decreased soluble and insoluble A 𝛃 , reduced amyloid plaque burden, and ameliorated neuroinflammation (9).”
From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [9]
Loss of IDOL in microglia increases LDLR protein levels, which in turn facilitates ApoE and Aβ uptake and clearance by microglia.
“Loss of IDOL in microglia increases LDLR protein levels, which in turn facilitates ApoE and A 𝛃 uptake and clearance by microglia.”
From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [9]
E3 ubiquitin ligase IDOL is a negative regulator of LDLR protein levels in microglia and neurons.
“We previously identified E3 ubiquitin ligase IDOL as a negative regulator of LDLR proteins levels in microglia and neurons (9).”
From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [9]
IDOL plays a primary role in regulating brain LDLR protein and has a limited effect on hepatic LDLR levels in mice.
“IDOL plays a primary role in regulating brain LDLR protein and has a limited effect on hepatic LDLR levels in mice”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Choi et al 2015
Sample sizes were determined based on statistical power calculations from prior experience and other studies in the literature.
“Sample sizes were determined based on the statistical power calculations from our experiences and other studies in the literature (26, 66, 67).”
From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [26]
The Materials and Methods section ('Statistical analysis'; page not available) says where sample sizes are reported and how P values were calculated. It does not say that sample sizes were determined by power calculations based on prior experience or other studies; searches for those terms found no supporting passage in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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The effects of ABCA1 on cholesterol efflux and Aβ levels <i>in vitro</i> and <i>in vivo</i>
Burns, M. P., Vardanian, L., Pajoohesh‐Ganji, A., Wang, L., Cooper, M., Harris, D. C., Duff, K., & Rebeck, G. W. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03925.x · Cited by 106 · see citing works
Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice
Cao, D., Fukuchi, K.-I., Wan, H., Kim, H., & Li, L. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.09.011 · Cited by 106 · see citing works
PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain
Liu, M., Wu, G., Baysarowich, J., Kavana, M., Addona, G. H., Bierilo, K. K., Mudgett, J. S., Pavlovic, G., Sitlani, A., Renger, J. J., et al. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m006635 · Cited by 98 · see citing works
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The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice
Hong, C., Marshall, S. M., McDaniel, A. L., Graham, M., Layne, J. D., Cai, L., Scotti, E., Boyadjian, R., Kim, J., Chamberlain, B. T., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.001 · Cited by 87 · see citing works
Self-citationThe IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor
Zhang, L., Fairall, L., Goult, B. T., Calkin, A. C., Hong, C., Millard, C. J., Tontonoz, P., & Schwabe, J. W. R. (2011) · Genes & Development · doi:10.1101/gad.2056211 · Cited by 86 · see citing works
Self-citationWeissglas-Volkov, D., Calkin, A. C., Tusie-Luna, T., Sinsheimer, J. S., Zelcer, N., Riba, L., Tino, A. M. V., Ordoñez-Sánchez, M. L., Cruz-Bautista, I., Aguilar-Salinas, C. A., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45504 · Cited by 66 · see citing works
Self-citationModulation of Aβ Deposition in APP Transgenic Mice by an Apolipoprotein E Null Background
IRIZARRY, M. C., REBECK, G. W., CHEUNG, B., BALES, K., PAUL, S. M., HOLZMAN, D., & HYMAN, B. T. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06919.x · Cited by 66 · see citing works
Calkin, A. C., Goult, B. T., Zhang, L., Fairall, L., Hong, C., Schwabe, J. W. R., & Tontonoz, P. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1111589108 · Cited by 62 · see citing works
Self-citationReconstituted Discoidal ApoE-Phospholipid Particles Are Ligands for the Scavenger Receptor BI
Li, X., Kan, H.-Y., Lavrentiadou, S. N., Krieger, M., & Zannis, V. I. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200658200 · Cited by 57 · see citing works
Calkin, A. C., Lee, S. D., Kim, J., van Stijn, C. M. W., Wu, X., Lusis, A. J., Hong, C., Tangirala, R. K., & Tontonoz, P. (2014) · Circulation Research · doi:10.1161/circresaha.115.304440 · Cited by 26 · see citing works
Self-citationPreparation and Coculture of Neurons and Glial Cells
Viviani, B. (2006) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb0207s32 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Liver X receptors in lipid signalling and membrane homeostasis
Wang, B., & Tontonoz, P. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0037-x · Cited by 722 · see citing works
Self-citationAmyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions
Ma, C., Hong, F., & Yang, S. (2022) · Molecules · doi:10.3390/molecules27041210 · Cited by 243 · see citing works
Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease
Liao, F., Yoon, H., & Kim, J. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000383 · Cited by 191 · see citing works
Self-citationLXR Regulation of Brain Cholesterol: From Development to Disease
Courtney, R., & Landreth, G. E. (2016) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.03.018 · Cited by 176 · see citing works
“The IDOL KO appeared to facilitate microglial clearance of Aβ, likely through permitting increased expression of LDLR that can act as a receptor for apoE, Aβ, or complexed apoE/Aβ species [30].”
BackgroundThe role of ubiquitin proteasomal system and autophagy-lysosome pathway in Alzheimer’s disease
Zhang, Y., Chen, X., Zhao, Y., Ponnusamy, M., & Liu, Y. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0013 · Cited by 99 · see citing works
“In AD patients as well as in transgenic mice with Aβ, the downregulation of E1 and E2 enzymes, the oxidation of DUBs, the accumulation of mutated ubiquitin, and the alterations of proteasome subunits are observed (Choi et al., 2015).”
The Ubiquitin System in Alzheimer’s Disease
Harris, L. D., Jasem, S., & Licchesi, J. D. F. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-38266-7_8 · Cited by 76 · see citing works
Exploring the Promise of Targeting Ubiquitin-Proteasome System to Combat Alzheimer’s Disease
Mamun, A. A., Uddin, M. S., Kabir, M. T., Khanum, S., Sarwar, M. S., Mathew, B., Rauf, A., Ahmed, M., & Ashraf, G. M. (2020) · Neurotoxicity Research · doi:10.1007/s12640-020-00185-1 · Cited by 63 · see citing works
Yuan, T., Chu, C., Shi, R., Cui, T., Zhang, X., Zhao, Y., Shi, X., Yan, H., Pan, J., Qian, R., et al. (2019) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.9b01436 · Cited by 64 · see citing works
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
Karahan, H., Smith, D. C., Kim, B., Dabin, L. C., Al-Amin, M. M., Wijeratne, H. R. S., Pennington, T., Viana di Prisco, G., McCord, B., Lin, P. B.-C., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe3954 · Cited by 53 · see citing works
Self-citationRole of Receptors in Relation to Plaques and Tangles in Alzheimer’s Disease Pathology
Sharma, K., Pradhan, S., Duffy, L. K., Yeasmin, S., Bhattarai, N., & Schulte, M. K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222312987 · Cited by 58 · see citing works
Zhang, X., Yuan, T., Chen, X., Liu, X., Hu, J., & Liu, Z. (2023) · Progress in Lipid Research · doi:10.1016/j.plipres.2023.101256 · Cited by 50 · see citing works
Ubiquitin-mediated regulation of sterol homeostasis
van den Boomen, D. J. H., Volkmar, N., & Lehner, P. J. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.04.010 · Cited by 41 · see citing works
van Loon, N. M., Ottenhoff, R., Kooijman, S., Moeton, M., Scheij, S. S., Abbing, R. L. P. R., Gijbels, M. J., Levels, J. H. M., Sorrentino, V., Berbée, J. F. P., et al. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311168 · Cited by 28 · see citing works
IDOL regulates systemic energy balance through control of neuronal VLDLR expression
Lee, S. D., Priest, C., Bjursell, M., Gao, J., Arneson, D. V., Ahn, I. S., Diamante, G., van Veen, J. E., Massa, M. G., Calkin, A. C., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0127-7 · Cited by 26 · see citing works
Self-citationProtein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease
Dhakal, S., & Macreadie, I. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218014 · Cited by 25 · see citing works
van Loon, N. M., Lindholm, D., & Zelcer, N. (2019) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000593 · Cited by 23 · see citing works
SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1
Wang, J.-Q., Lin, Z., Li, L., Zhang, S.-Y., Li, W., Liu, W., Song, B.-L., & Luo, J. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.015420 · Cited by 22 · see citing works
“However, our findings are still of great importance considering that IDOL deficiency facilitates LDLR-dependent clearance of ApoE and β-amyloid in the brain, thereby reducing the formation and deposition of amyloid plaques and improving cognitive function in the mouse model of Alzheimer’s disease (46, 47).”
BackgroundUnderstanding the Role of miR-33 in Brain Lipid Metabolism: Implications for Alzheimer's Disease
Jaouen, F., & Gascon, E. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.4571-15.2016 · Cited by 20 · see citing works
“This is relevant to AD because there is extensive literature support for a connection between cholesterol and -amyloid homeostasis (Puglielli et al., 2001; Jiang et al., 2008; Choi et al., 2015).”
BackgroundGold, A., Kaye, S. D., Gao, J., & Zhu, J. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00370 · Cited by 20 · see citing works
Self-citationRegulation of intestinal LDLR by the LXR-IDOL axis
van Loon, N. M., van Wouw, S. A. E., Ottenhoff, R., Nelson, J. K., Kingma, J., Scheij, S. S., Moeton, M., & Zelcer, N. (2020) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2020.10.898 · Cited by 19 · see citing works
Wu, B., Liu, Y., Li, H., Zhu, L., Zeng, L., Zhang, Z., & Peng, W. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.391305 · Cited by 20 · see citing works
Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets
Wang, N.-Q., Sun, P.-X., Shen, Q.-Q., & Deng, M.-Y. (2025) · Molecular Neurobiology · doi:10.1007/s12035-024-04672-w · Cited by 19 · see citing works
“However, other studies have revealed that in primary microglia from Idol −/− mice, upregulation of LDLR expression promotes the endocytosis of APOE, Aβ, or the APOE/Aβ complex, reducing amyloid plaque burden and improving neuroinflammation [134].”
Yu, Q., Zheng, H., & Zhang, Y. (2021) · Vascular Pharmacology · doi:10.1016/j.vph.2021.106878 · Cited by 16 · see citing works
The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms
Ndoj, K., Meurs, A., Papaioannou, D., Bjune, K., & Zelcer, N. (2024) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.119082 · Cited by 16 · see citing works
Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice
Gao, J., Littman, R., Diamante, G., Xiao, X., Ahn, I. S., Yang, X., Cole, T. A., & Tontonoz, P. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00518-19 · Cited by 15 · see citing works
“Proteins were sequentially extracted from brain tissues with RIPA, and 5 M guanidine buffer in the presence of protease inhibitors as described previously (9).”
BackgroundMethodInfluentialSelf-citationMartinelli, L., Adamopoulos, A., Johansson, P., Wan, P., Gunnarsson, J., Guo, H., Boyd, H., Zelcer, N., & Sixma, T. K. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014349 · Cited by 14 · see citing works
Yong, J., Villalta, J. E., Vu, N., Kukurugya, M. A., Olsson, N., López, M. P., Lazzari-Dean, J. R., Hake, K., McAllister, F. E., Bennett, B. D., et al. (2023) · eLife · doi:10.7554/elife.86194 · Cited by 12 · see citing works
Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques
Kaye, S. D., Gold, A., Lin, D., Chen, M., Zhu, J., & Gao, J. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115272 · Cited by 11 · see citing works
“Conversely, Liang et al. observed increased diffuse and compact plaques in WD-fed mice, along with disrupted microglial fatty acid metabolism and increased lipid droplet aggregation 43 .”
Self-citationChauhan, P., Wadhwa, K., & Singh, G. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.156109 · Cited by 11 · see citing works
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“In combination with deletion of Idol, an E3 ubiquitin ligase expressed in microglia, also reduces ApoE in the brain [54].”
Jia, S., Li, Q., Rui, X., Qin, W., Zhang, W., Dou, J., & Zhang, X. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1730206 · Cited by 8 · see citing works
“Idol is a negative regulator of LDLR in microglia, and the absence of Idol in microglia increases the level of LDLR protein, which in turn promotes the uptake and clearance of ApoE and A β by microglia (Choi et al., 2015).”
Rahman, M. A., Hossain, S., Abdullah, N., & Aminudin, N. (2019) · AIMS neuroscience · doi:10.3934/neuroscience.2019.4.299 · Cited by 7 · see citing works
“Idol had been implicated as the principal regulator of LDLR degradation and an inhibitor to the clearance of brain level of both Apo E and Aβ [37].”
Haskell, A. K., Kulas, J. A., Carter, W., Javens‐Wolfe, J., Hinkel, R. D., Moussaif, M., Smiley, J. S., Lazaro, O., Robertson, S., Palkowitz, A. D., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71117 · Cited by 6 · see citing works
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Self-citationIDOL in metabolic, neurodegenerative and cardiovascular disease
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“8 Ubiquitin was fi rst identi fi ed within senile plaques and neuro fi brillary tangles in 1987.”
Huang, N., Hong, R., Cui, X., Cao, L., Shi, L., Chen, B., Su, Y., Xu, X., Hua, C., & Ying, T. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04297-2 · Cited by 5 · see citing works
“As a ligand, LRP1 regulates Aβ metabolism and brain homeostasis in the brain, impairment of which likely contributes to AD patholohical development [28–31].”
Idolizing the clearance of Amyloid-β by microglia
van Loon, N. M., & Zelcer, N. (2016) · Annals of Translational Medicine · doi:10.21037/atm.2016.11.63 · Cited by 3 · see citing works
“Choi and colleagues are the first to describe a role for the E3 ubiquitin ligase IDOL in the pathophysiology of AD (17).”
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Self-citationAs a matter of fat: Emerging roles of lipid‐sensitive E3 ubiquitin ligases
Gawden‐Bone, C. M., Lehner, P. J., & Volkmar, N. (2023) · BioEssays · doi:10.1002/bies.202300139 · Cited by 2 · see citing works
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Understanding Neurodegeneration and Neuroprotection Through Genetic Screens in Drosophila
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Wang, L., Liu, J., Peng, Y.-Z., Zhang, C., Zou, W., Liu, F., Zhan, K., & Zhang, P. (2022) · Natural Product Communications · doi:10.1177/1934578x221141162
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IDOL alleviates the body weight by upregulating UCP ‐1 in mice
Guan, H., Wang, L., Tang, C., Xu, H., Xiang, A., Chen, X., Yu, Q., & Xu, L. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16127
E3 Ubiquitin Ligases in Alzheimer’s Disease
Gavilán, E. (2026) · Springer eBooks · doi:10.1007/978-981-95-6099-8_10
HUWE1 interactomes reveal sex-specific networks of nucleic acid-binding proteins
Escarcega, R. D., Kumar, M. J. V., Abdul, A., Bommineni, R., Manwani, B., Jung, S. Y., & Tsvetkov, A. S. (2026) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2026.104115
- Authors
- Choi, J., Gao, J., Kim, J., Hong, C., Kim, J., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Mayo Clinic (US)
- Corresponding author
- Choi, Jinkuk
- Gao, Jie
- Kim, Jaekwang
- Kim, Jungsu
- Tontonoz, Peter
- Venue
- Science Translational Medicine
- Published
- 2015-11-18
- Volume
- 7
- Issue
- 314
- Pages
- 314ra184-314ra184
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC7153735
- OpenAlex
- W2177820706
- Semantic Scholar
- 3380bfa198ec37c8c9e74a4559545f1ab160868b
- Cited by
- 49
- References
- 58
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 8 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 4
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (HL066088, NS069329)
- Alzheimer's Association
- BrightFocus Foundation (A2012421)
- GHR
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- idols, E3 ubiquitin ligase, LDL receptor, apolipoprotein E, amyloid-beta clearance, Alzheimer's disease, amyloid plaques, high-density lipoprotein, neuroinflammation, LDLR degradation
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Apolipoproteins E, Brain, Cell Line, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Phenotype, Receptors, LDL, Time Factors, Amyloid beta-Peptides, Mice, Knockout, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Plaque, Amyloid, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.
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