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Cited by 16Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsAutophagy in Disease and Therapy

Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice

Open access
Gao, Jie, Littman, Russell, Diamante, Graciel, Xiao, Xu, Ahn, In Sook, Yang, Xia, Cole, Tracy A., Tontonoz, Peter·2020·Molecular and Cellular Biology
DOI 10.1128/mcb.00518-19PMC PMC7108818
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Abstract

Brain lipoprotein receptors have been shown to regulate the metabolism of ApoE and β-amyloid (Aβ) and are potential therapeutic targets for Alzheimer’s disease (AD). Previously, we identified E3 ubiquitin ligase IDOL as a negative regulator of brain lipoprotein receptors. Genetic ablation of Idol increases low-density lipoprotein receptor protein levels, which facilitates Aβ uptake and clearance by microglia. In this study, we utilized an antisense oligonucleotide (ASO) to reduce IDOL expression therapeutically in the brains of APP/PS1 male mice. ASO treatment led to decreased Aβ pathology and improved spatial learning and memory. Single-cell transcriptomic analysis of hippocampus revealed that IDOL inhibition upregulated lysosomal/phagocytic genes in microglia. Furthermore, clustering of microglia revealed that IDOL-ASO treatment shifted the composition of the microglia population by increasing the prevalence of disease-associated microglia. Our results suggest that reducing IDOL expression in the adult brain promotes the phagocytic clearance of Aβ and ameliorates Aβ-dependent pathology. Pharmacological inhibition of IDOL activity in the brain may represent a therapeutic strategy for the treatment of AD.

Verified 2026-10-19 · 3 references not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

In APP/PS1 male mice, intracerebroventricular antisense oligonucleotide knockdown of IDOL reduced amyloid plaque burden and improved Morris water maze performance. Single-cell hippocampal transcriptomics linked IDOL reduction to increased microglial lysosomal/phagocytic gene expression and a shift toward disease-associated microglia.

Key findings

  • IDOL ASO showed an IC50 of 12.5 µg/mouse and an estimated half-life of 9 weeks; a single 40-µg i.c.v. dose reduced IDOL mRNA by at least 80% across hippocampus, cortex, thalamus, and cerebellum, and increased LDLR, VLDLR, and ApoER2 protein levels.
  • In APP/PS1 mice, IDOL ASO reduced Aβ plaque area by >50% and fibrillar plaque load by >50%, lowered soluble and insoluble Aβ40/Aβ42, reduced total amyloid and ApoE by Western blot, and decreased plaque density, average plaque size, and large plaques (>1,000 µm²; plaques >2,000 µm² were rarely observed in the ASO group).
  • IDOL ASO reduced plaque-associated neuritic dystrophy (LAMP1 and APP staining), reduced GFAP-positive reactive astrocytes, and decreased microglial cell body size around plaques; Iba1-positive area normalized to plaque area did not differ between groups.
  • Morris water maze performance improved in ASO-treated APP/PS1 mice (less escape latency on days 4 and 5; more time and distance in the target quadrant), with no difference in fear conditioning; scRNA-seq of 14,682 hippocampal cells (6,888 PBS, 7,794 ASO) showed microglial lysosomal pathway enrichment and upregulated Ctsb, Ctsd, and CD63, plus a shift toward DAM-like microglia (22.45% PBS vs 35.36% ASO; P = 0.04154, Fisher exact test).

Methods

  • Male C57BL/6J and APP/PS1 mice received i.c.v. IDOL ASO or PBS; dosing studies used n = 5/group, pathology cohorts used n = 8–10/group, and behavior cohorts used n = 12/group, with treatment starting at 3 months and boosters at 6 and 9 months.
  • Outcomes included qPCR, Western blot, Aβ40/Aβ42 ELISA, immunohistochemistry/immunofluorescence for plaques, neuritic dystrophy, astrocytes, and microglia, plus Morris water maze and fear conditioning.
  • Hippocampal single-cell RNA sequencing used Drop-seq with n = 3/group, followed by Seurat clustering (UMAP/t-SNE), differential expression at FDR < 0.05, and pathway analysis.

Limitations

  • Stated in the paper: mechanisms by which increased LDLR enhances microglial phagocytosis remain to be clarified; whether effects depend on ApoE and different ApoE alleles requires future experiments; the exact roles of the identified microglial subgroups are unclear; and a contribution of neuronal ApoER2 to neuroprotection cannot be ruled out.
  • Evident from the text: all APP/PS1 experiments used male mice, so sex-specific effects were not assessed.
  • Evident from the text: the scRNA-seq findings are correlative and based on n = 3 mice/group; cell-type-specific IDOL deletion experiments were described as ongoing rather than completed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1128/mcb.00518-19

Cites

47 of 51 references verified1 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

25 of 41 cited sources checked · 18 supported · 0 flagged · accuracy not yet measured

  • Premisecitation
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 2

    ApoE independently influences several key factors that drive pathogenesis of Alzheimer's disease, including β-amyloidosis, tauopathy, and synaptic dysfunction.

    “ApoE has been shown to independently influence several key factors that drive pathogenesis of AD, including 𝛃 -amyloidosis, tauopathy, and synaptic dysfunction (1-3).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [1] 1. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-923. https://doi.org/10.1126/science.8346443. source
    • cites [2] 2. Liu CC, Kanekiyo T, Xu H, Bu G. 2013. Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. Nat Rev Neurol 9:106-118. https://doi.org/10.1038/nrneurol.2012.263. source
    • cites [3] 3. Shi Y, Alzheimer's Disease Neuroimaging Initiative, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer's DNI, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. 2017. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523-527. https://doi.org/10.1038/nature24016. source

      The paper’s Abstract says ApoE influences Aβ deposition and reports that ApoE affects tau pathogenesis independently of Aβ pathology. It also reports neuronal injury and reduced neurite arborization, but the passages do not establish an independent effect on synaptic dysfunction; that part of the cited sentence is unsupported by this source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 2

    Lowering ApoE levels prior to the formation of Aβ plaque in APP/PS1 mice reduces Aβ plaque pathology.

    “lowering ApoE levels prior to the formation of A 𝛃 plaque in APP/PS1 mice reduces A 𝛃 plaque pathology (4).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] 4. Huynh TV, Liao F, Francis CM, Robinson GO, Serrano JR, Jiang H, Roh J, Finn MB, Sullivan PM, Esparza TJ, Stewart FR, Mahan TE, Ulrich JD, Cole T, Holtzman DM. 2017. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of beta-amyloidosis. Neuron 96: 1013-1023. https://doi.org/10.1016/j.neuron.2017.11.014. source
  • Findingcitation
    § RESULTS · p. 10

    Subgroups 2 and 3 resembled disease-associated microglia (DAM), with high expression of Cst7, Trem2, and ApoE.

    “whereas subgroups 2 and 3 resembled disease-associated microglia (DAM), with high expression of marker genes such as Cst7 , Trem2 , and ApoE (23)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] 23. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. 2017. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169: 1276-1290. https://doi.org/10.1016/j.cell.2017.05.018. source
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.
  • Premisecitation
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 2

    ApoE impairs Aβ clearance from the brain interstitial fluid.

    “and to impair its clearance from the brain interstitial fluid (6).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] 6. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. 2011. Human apoE isoforms differentially regulate brain amyloid𝛃 peptide clearance. Sci Transl Med 3:89ra57. https://doi.org/10.1126/scitranslmed.3002156. source

      The Results section reports reduced Aβ clearance from brain interstitial fluid in mice expressing apoE4 compared with mice expressing apoE3 or apoE2. The claim omits that isoform-specific comparison and instead says apoE generally impairs clearance; the reported experiment does not establish that broader claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation
    § DISCUSSION · p. 15

    Overexpression of the LDLR in the brain enhances Aβ clearance.

    “overexpression of the LDLR in the brain enhances A 𝛃 clearance”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] 8. Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM. 2009. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron 64:632-644. https://doi .org/10.1016/j.neuron.2009.11.013. source
  • May combine two claims. 18
  • Classified as probably not a substantial claim. 24
  • The quote only partly states this claim. 2

  • May combine two claims.

    Premisecitation
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 3

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] 9. Choi J, Gao J, Kim J, Hong C, Kim J, Tontonoz P. 2015. The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and A 𝛃 amyloidosis. Sci Transl Med 7:314ra184. https://doi.org/10.1126/ scitranslmed.aad1904. source

  • May combine two claims.

    Premisecitation
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 3

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] 9. Choi J, Gao J, Kim J, Hong C, Kim J, Tontonoz P. 2015. The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and A 𝛃 amyloidosis. Sci Transl Med 7:314ra184. https://doi.org/10.1126/ scitranslmed.aad1904. source

  • May combine two claims.

    Premisecitation
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 3

    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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] 9. Choi J, Gao J, Kim J, Hong C, Kim J, Tontonoz P. 2015. The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and A 𝛃 amyloidosis. Sci Transl Med 7:314ra184. https://doi.org/10.1126/ scitranslmed.aad1904. source

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

    Premisecitation
    § DISCUSSION · p. 15

    DAM associates with amyloid plaques.

    “DAM has been shown to associate with amyloid plaques”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] 23. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. 2017. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169: 1276-1290. https://doi.org/10.1016/j.cell.2017.05.018. source

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

    Premisecitation
    § DISCUSSION · p. 15

    The existence of DAM in mice and humans has recently been confirmed in tauopathy AD models, aging, and other neurodegenerative diseases such as ALS and multiple sclerosis.

    “The existence of DAM in mice and humans has recently been confirmed in tauopathy AD models (26, 27), aging (27, 28), and other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) (29) and multiple sclerosis (30).”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [26] 26. Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee SH, Haddick PCG, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP, Hansen DV. 2018. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer's disease not evident in mouse models. Cell Rep 22:832-847. https://doi.org/10.1016/j.celrep.2017.12.066. source

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

    • cites [27] 27. Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP, Lelios I, Heppner FL, Kipnis J, Merkler D, Greter M, Becher B. 2018. Highdimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48:380-395. https://doi.org/10.1016/j.immuni.2018.01.011. source
    • cites [28] 28. Olah M, Patrick E, Villani AC, Xu J, White CC, Ryan KJ, Piehowski P, Kapasi A, Nejad P, Cimpean M, Connor S, Yung CJ, Frangieh M, McHenry A, Elyaman W, Petyuk V, Schneider JA, Bennett DA, De Jager PL, Bradshaw EM. 2018. A transcriptomic atlas of aged human microglia. Nat Commun 9:539. https://doi.org/10.1038/s41467-018-02926-5. source

      This source is cited for the aging portion of the sentence. Its Results section ('Identification of human microglia genes affected by aging'; page unavailable) reports age-related changes in human microglia, and its Discussion describes a distinctive aged-human-microglia phenotype. It does not identify that phenotype as DAM or confirm DAM in mice; the disease examples are assigned to other citations in the sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [29] 29. Spiller KJ, Restrepo CR, Khan T, Dominique MA, Fang TC, Canter RG, Roberts CJ, Miller KR, Ransohoff RM, Trojanowski JQ, Lee VM. 2018. Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat Neurosci 21: 329-340. https://doi.org/10.1038/s41593-018-0083-7. source

      The Results section on transcriptomic profiling (page unavailable) reports that genes previously called DAM were upregulated in microglia from an ALS-relevant mouse model during both late disease and early recovery. This supports the ALS mouse-model portion of the citation, but the paper does not establish a DAM population in humans: its human ALS analysis assesses reactive microgliosis, not DAM identity. The other diseases in the citing sentence have separate citations and are not assessed here. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [30] 30. Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O. 2017. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47: 566-581.e9. https://doi.org/10.1016/j.immuni.2017.0 source

      The Results section ('Reciprocal induction of APOE and suppression of TGFβ signaling'; page unavailable) identifies an MGnD microglial phenotype in EAE, a mouse model of multiple sclerosis. This supports the multiple-sclerosis-model portion of the cited claim, but the paper does not establish that phenotype in humans with multiple sclerosis; its human specimens were from AD patients. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation
    § DISCUSSION · p. 15

    High-level expression of genes in phagocytic and lipid metabolism pathways is the molecular signature of disease-associated microglia (DAM), a recently identified subset of CNS-resident microglia in the 5XFAD mouse model.

    “High-level expression of genes in phagocytic and lipid metabolism pathways is the molecular signature of disease-associated microglia (DAM), a recently identified subset of CNS-resident microglia in the 5XFAD mouse model (23).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] 23. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. 2017. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169: 1276-1290. https://doi.org/10.1016/j.cell.2017.05.018. source

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

    Premisecitation
    § DISCUSSION · p. 15

    Aβ turnover and clearance in the mouse brain in vivo is strongly dependent upon ApoE isoform.

    “A 𝛃 turnover and clearance in the mouse brain in vivo is strongly dependent upon ApoE isoform (6)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] 6. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. 2011. Human apoE isoforms differentially regulate brain amyloid𝛃 peptide clearance. Sci Transl Med 3:89ra57. https://doi.org/10.1126/scitranslmed.3002156. source

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

    Premisecitation
    § DISCUSSION · p. 16

    IDOL-dependent regulation of synaptic ApoER2 has been implicated in the modulation of dendritic filopodium initiation and synapse maturation during the early postnatal stage.

    “IDOL-dependent regulation of synaptic ApoER2 has been implicated in the modulation of dendritic filopodium initiation and synapse maturation during the early postnatal stage (36).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] 36. Gao J, Marosi M, Choi J, Achiro JM, Kim S, Li S, Otis K, Martin KC, Portera-Cailliau C, Tontonoz P. 2017. The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning. Elife 6:e29178. https://doi.org/10.7554/eLife.29178. source

  • May combine two claims.

    Premisecitation
    § DISCUSSION · p. 15

    LDLR is an ApoE receptor known to regulate brain Aβ clearance.

    “LDLR is an ApoE receptor known to regulate brain A 𝛃 clearance.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [24] 24. Cao D, Fukuchi K, Wan H, Kim H, Li L. 2006. Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice. Neurobiol Aging 27:1632-1643. https://doi.org/10.1016/j .neurobiolaging.2005.09.011. source
    • cites [25] 25. Katsouri L, Georgopoulos S. 2011. Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model. PLoS One 6:e21880. https://doi.org/10.1371/journal.pone .0021880. source
    • cites [8] 8. Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM. 2009. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron 64:632-644. https://doi .org/10.1016/j.neuron.2009.11.013. source

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

    Premisecitation
    § DISCUSSION · p. 16

    IDOL is expressed in neurons, where it posttranslationally regulates the level of neuronal lipoprotein receptors, including ApoER2/LRP8 and VLDLR.

    “IDOL is also expressed in neurons, where it posttranslationally regulates the level of neuronal lipoprotein receptors, including ApoER2/LRP8 and VLDLR.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [36] 36. Gao J, Marosi M, Choi J, Achiro JM, Kim S, Li S, Otis K, Martin KC, Portera-Cailliau C, Tontonoz P. 2017. The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning. Elife 6:e29178. https://doi.org/10.7554/eLife.29178. source

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

    Premisecitation
    § DISCUSSION · p. 15

    DAM actively participates in the dismantling and digestion of amyloid plaques.

    “actively participate in the dismantling and digestion of the amyloid plaques (23)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] 23. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. 2017. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169: 1276-1290. https://doi.org/10.1016/j.cell.2017.05.018. source

      The Results state that the findings “suggest that DAM actively participate in the dismantling and digestion of the amyloid plaques.” The citing sentence presents that interpretation as an established fact, omitting the source’s qualification. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation
    § DISCUSSION · p. 15

    ApoE facilitates the microglial response to amyloid plaque pathology.

    “It has been reported that ApoE facilitates the microglial response to amyloid plaque pathology (31).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] 31. Colonna M, Butovsky O. 2017. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35: 441-468. https://doi.org/10.1146/annurev-immunol-051116-052358. source

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

    Premisecitation
    § RESULTS · p. 10

    DAM cells are abundant near amyloid plaques and actively participate in phagocytic removal of amyloid plaques.

    “It has been shown that DAM cells are abundant near amyloid plaques and actively participate in phagocytic removal of amyloid plaques (23).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] 23. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. 2017. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169: 1276-1290. https://doi.org/10.1016/j.cell.2017.05.018. source

      The Results (page unavailable) locate DAM-marked microglia near Aβ plaques and report intracellular Aβ particles in these cells. The paper says these findings *suggest* that DAM participate in dismantling and digesting plaques; it does not establish active plaque removal as a demonstrated fact. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • The quote only partly states this claim.

    Findingown data
    § RESULTS · p. 3

    Western blot analysis confirmed IDOL ASO treatment led to reduction of ApoE levels.

    “and ApoE levels (Fig. 2E).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.
    • Rests on an assumption: ApoE primarily influences Alzheimer's disease pathology via its effects on Aβ metabolism.

  • May combine two claims.

    Findingown data
    § RESULTS · p. 10

    Each cell cluster contained cells from all six samples without batch effects.

    “Each cell cluster contained cells from all six samples without batch effects”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.

  • May combine two claims.

    Findingown data
    § RESULTS · p. 6

    Microglia in IDOL ASO-treated group were less hypertrophic and displayed reduced cell body size compared to vehicle-treated group.

    “microglia in the IDOL ASO-treated group were less hypertrophic and displayed a reduced cell body size compared to those in the vehicle-treated group (Fig. 4C).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.
    • Rests on an assumption: Aβ accumulation and aggregation are key initiators of complex pathological changes in the brain that culminate in neurodegeneration years later.

  • May combine two claims.

    Findingown data
    § RESULTS · p. 7

    Improvement in performance could not be attributed to vision or locomotor differences, since both groups performed similarly in visible platform test and exhibited comparable swimming speed.

    “This improvement in performance could not be attributed to vision or locomotor differences, since both groups performed similarly in the visible platform test (Fig. 5C, left) and exhibited comparable swimming speed (Fig. 5C, right).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.

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

    Findingown data
    § RESULTS · p. 9

    scRNA-seq obtained data for total 14,682 cells (6,888 PBS, 7,794 ASO) after quality control filtering.

    “We obtained data for a total of 14,682 cells (6,888 from the PBS group and 7,794 from the ASO-treated group) after quality control filtering.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.

  • May combine two claims.

    Findingown data
    § RESULTS · p. 3

    mRNA levels of LDLR, VLDLR, and ApoER2 remain unchanged in IDOL ASO-treated mice.

    “despite the fact that their mRNA levels remain unchanged (data not shown)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.

  • May combine two claims.

    Findingown data
    § RESULTS · p. 3

    IDOL ASO treatment did not affect body weight or gross behavior.

    “We did not observe changes in body weight or gross behavior associated with IDOL ASO treatment in our study.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.

  • The quote only partly states this claim.

    Findingown data
    § DISCUSSION · p. 15

    IDOL inhibition led to an improvement in spatial memory in adult APP/PS1 mice.

    “an improvement in spatial memory”
    Quote in the paperSubstantial claim

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

    Findingnone given
    § MATERIALS AND METHODS · p. 16

    The half-life of ASO was estimated around 9 weeks.

    “The half-life of ASO was estimated around 9 weeks.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § MATERIALS AND METHODS · p. 16

    When administrating IDOL ASO to a cohort of wild-type mice (two groups, n = 5 for each group), IDOL mRNA levels were downregulated 92 and 62%, respectively, 1 week or 2 months after ASO administration.

    “When administrating IDOL ASO to a cohort of wild-type mice (two groups, n = 5 for each group), IDOL mRNA levels were downregulated 92 and 62%, respectively, 1 week or 2 months after ASO administration.”
    Quote in the paperSubstantial claim

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

    Interpretationown data
    § RESULTS · p. 7

    Failure to detect a difference in fear conditioning may be due to performance in both groups being comparable to wild-type mice.

    “The failure to detect a difference in this test may be due to the fact that performance in both groups was comparable to wild-type mice (Fig. 1E).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 2

    Among ApoE receptors, LDLR and neuronal LRP1 are the principal regulators of ApoE metabolism, acting to mediate the uptake and degradation of ApoE-containing lipoprotein particles by brain cells.

    “Among ApoE receptors, LDLR and neuronal LRP1 are the principal regulators of ApoE metabolism, acting to mediate the uptake and degradation of ApoE-containing lipoprotein particles by brain cells (7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] 7. Holtzman DM, Herz J, Bu G. 2012. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2:a006312. https://doi.org/10.1101/cshperspect.a006312. source

  • May combine two claims.

    Interpretationown data
    § RESULTS · p. 6

    Pharmacological inhibition of brain IDOL activity is sufficient to reduce Aβ levels and plaque burdens in APP/PS1 mice.

    “Together, these results suggested that pharmacological inhibition of brain IDOL activity is sufficient to reduce A 𝛃 levels and plaque burdens in APP/PS1 mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.
    • Rests on an assumption: Aβ accumulation and aggregation are key initiators of complex pathological changes in the brain that culminate in neurodegeneration years later.

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

    Premisecitation
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 2

    ApoE promotes Aβ aggregation.

    “ApoE has also been reported to promote A 𝛃 aggregation (5)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] 5. Ma J, Yee A, Brewer HB, Das S, Potter H. 1994. Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372:92-94. https://doi.org/10.1038/372092a0. source

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

    Premisecitation
    § DISCUSSION · p. 16

    CSF-1 stimulates clearance of Aβ.

    “stimulates clearance of A 𝛃 (35)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] 35. Mitrasinovic OM, Vincent VA, Simsek D, Murphy GM. 2003. Macrophage colony stimulating factor promotes phagocytosis by murine microglia. Neurosci Lett 344:185-188. https://doi.org/10.1016/S0304-3940(03) 00474-9. source

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

    Interpretationreasoning
    § DISCUSSION · p. 16

    These four subgroups may contribute differently to the pathogenesis of AD.

    “It is plausible that these four subgroups may contribute differently to the pathogenesis of AD.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § DISCUSSION · p. 16

    CSF-1 increases microglial phagocytic activity.

    “It has been shown that CSF-1 increases microglial phagocytic activity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] 35. Mitrasinovic OM, Vincent VA, Simsek D, Murphy GM. 2003. Macrophage colony stimulating factor promotes phagocytosis by murine microglia. Neurosci Lett 344:185-188. https://doi.org/10.1016/S0304-3940(03) 00474-9. source

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

    Premisecitation
    § DISCUSSION · p. 16

    Microglial activation is mediated by a CSF-1/CSF-1R autocrine loop, which results in reactive microgliosis and the release of inflammatory cytokines.

    “Several lines of evidence suggest that microglial activation is mediated by a CSF-1/CSF-1R autocrine loop, which results in reactive microgliosis and the release of inflammatory cytokines (33, 34).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] 33. Chitu V, Stanley ER. 2006. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol 18:39-48. https://doi.org/10.1016/j .coi.2005.11.006. source
    • cites [34] 34. Hao AJ, Dheen ST, Ling EA. 2002. Expression of macrophage colonystimulating factor and its receptor in microglia activation is linked to teratogen-induced neuronal damage. Neuroscience 112:889-900. https:// doi.org/10.1016/S0306-4522(02)00144-6. source

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § DISCUSSION · p. 15

    LDLR may enhance phagocytic activity of microglia through the ApoE pathway.

    “We reason that LDLR may enhance phagocytic activity of microglia through the ApoE pathway.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LDLR is a major metabolic receptor for ApoE.

  • May combine two claims.

    Interpretationown data
    § Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice · p. 2

    Reducing IDOL expression in the adult brain promotes the phagocytic clearance of Aβ and ameliorates Aβ-dependent pathology.

    “Our results suggest that reducing IDOL expression in the adult brain promotes the phagocytic clearance of A 𝛃 and ameliorates A 𝛃 -dependent pathology.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.
    • Rests on an assumption: APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.
    • Rests on an assumption: Aβ accumulation and aggregation are key initiators of complex pathological changes in the brain that culminate in neurodegeneration years later.

  • May combine two claims.

    Interpretationown data
    § DISCUSSION · p. 15

    The increased expression of lysosomal/phagocytic cell-related genes corresponds to enhanced clearance of soluble Aβ and reduced plaque deposition in the brains of APP/PS1 mice.

    “corresponding to the enhanced clearance of soluble A 𝛃 and reduced plaque deposition in the brains of APP/PS1 mice”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Microglia are professional phagocytes capable of clearing pathogenic Aβ in the brain.

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

    Premisecitation
    § DISCUSSION · p. 16

    CSF-1 mediates microglial-induced neurotoxicity by promoting the release of inflammatory cytokines.

    “CSF-1 also mediates microglial-induced neurotoxicity by promoting the release of inflammatory cytokines.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] 35. Mitrasinovic OM, Vincent VA, Simsek D, Murphy GM. 2003. Macrophage colony stimulating factor promotes phagocytosis by murine microglia. Neurosci Lett 344:185-188. https://doi.org/10.1016/S0304-3940(03) 00474-9. source

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

    Study design and conductnone given
    § MATERIALS AND METHODS · p. 16

    All mouse experiments were approved and performed under the guidelines of the Animal Care and Research Advisory Committees at the University of California, Los Angeles (UCLA).

    “All mouse experiments were approved and performed under the guidelines of the Animal Care and Research Advisory Committees at the University of California, Los Angeles (UCLA).”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § DISCUSSION · p. 16

    ApoER2 functionally couples to NMDA receptors.

    “ApoER2 has also been shown to functionally couple to NMDA receptors (37)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] 37. Beffert U, Weeber EJ, Durudas A, Qiu S, Masiulis I, Sweatt JD, Li WP, Adelmann G, Frotscher M, Hammer RE, Herz J. 2005. Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron 47-579. https://doi.org/10 .1016/j.neuron.2005.07.007. source

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

    Premisecitation
    § DISCUSSION · p. 16

    ApoER2 protects against the loss of cortical neurons during normal aging.

    “protect against the loss of cortical neurons during normal aging (38)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] 38. Beffert U, Nematollah Farsian F, Masiulis I, Hammer RE, Yoon SO, Giehl KM, Herz J. 2006. ApoE receptor 2 controls neuronal survival in the adult brain. Curr Biol 16:2446 -2452. https://doi.org/10.1016/j.cub .2006.10.029. source

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

    Study design and conductnone given
    § MATERIALS AND METHODS · p. 17

    The experimenter was blind to the genotype of the animals.

    “The experimenter was blind to the genotype of the animals.”
    Quote in the paperNot a substantial claim
39 of 39

  • The paper relies on this without support.

    IDOL ASO treatment effects are due to specific IDOL knockdown and not off-target effects.

    “This approach achieves close to maximum IDOL knockdown efficiency with minimal amount of ASO, thereby minimizing nonspecific effects.”

  • The paper relies on this without support.

    APP/PS1 male mice are a valid model of Alzheimer's disease amyloidosis and cognitive deficits.

    “a transgenic mouse model of A 𝛃 amyloidosis”

  • The paper relies on this without support.

    Aβ accumulation and aggregation are key initiators of complex pathological changes in the brain that culminate in neurodegeneration years later.

    “since 𝛃 -amyloid (A 𝛃 ) accumulation and aggregation are key initiators of complex pathological changes in the brain that culminate in neurodegeneration years later.”

  • The paper relies on this without support.

    ApoE primarily influences Alzheimer's disease pathology via its effects on Aβ metabolism.

    “Mounting evidence suggests that ApoE primarily influences AD pathology via its effects on A 𝛃 metabolism.”

  • The paper relies on this without support.

    ApoE exerts the greatest impact on amyloidosis during the initial seeding stage.

    “ApoE exerts the greatest impact on amyloidosis during the initial seeding stage;”

  • The paper relies on this without support.

    ApoE4 has a powerful impact on the development of late-onset AD.

    “ApoE4 has a powerful impact on the development of late-onset AD.”

  • The paper relies on this without support.

    LDLR is a major metabolic receptor for ApoE.

    “Since LDLR is a major metabolic receptor for ApoE”

  • The paper relies on this without support.

    CSF-1 is a key regulator of inflammatory responses in the brain.

    “CSF-1 is considered a key regulator of inflammatory responses in the brain.”

  • The paper relies on this without support.

    Microglia are professional phagocytes capable of clearing pathogenic Aβ in the brain.

    “Microglia are professional phagocytes capable of clearing targeted pathogens, cellular debris, and pathogenic A 𝛃 in the brain.”

  • The paper relies on this without support.

    Loss of IDOL in microglia enhances the uptake and clearance of Aβ.

    “Previous in vitro studies suggested that loss of IDOL in microglia enhances the uptake and clearance of A 𝛃 .”
10 of 10

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?

  • Inhibition of IDOL with an antisense oligonucleotide induces transcriptomic changes mainly in microglia populations.

    “Moreover, the inhibition of IDOL with an antisense oligonucleotide induced transcriptomic changes mainly in microglia populations, as detected by single‐cell RNA‐seq. 62”

    From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [62]

    The Results (pp. 9–10) describe single-cell RNA-seq of hippocampal cells from IDOL-ASO-treated APP/PS1 mice and report altered microglial gene expression. But the Results (p. 10) say that microglia and oligodendrocytes had the largest numbers of differentially expressed genes, so the claim that changes occurred mainly in microglia omits another prominently affected cell type. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Using an ASO to reduce IDOL expression in the brains of APP/PS1 male mice, IDOL reduction led to a significant increase of brain LDLR levels, decrease of apoE levels, and alleviation of amyloid pathology and cognitive decline.

    “Using an antisense oligonucleotide (ASO) to reduce IDOL expression in the brains of APP/PS1 male mice, it was demonstrated that IDOL reduction led to a significant increase of brain LDLR levels, decrease of apoE levels, and alleviation of amyloid pathology and cognitive decline”

    From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Gao et al 2020

    The Results (pp. 3, 6) report reduced ApoE and amyloid pathology and improved spatial learning and memory after IDOL-ASO treatment in male APP/PS1 mice. The Results (p. 3) also report increased brain LDLR protein, but the corresponding Western blot is identified as using wild-type mice (Fig. 1D, p. 4), not APP/PS1 mice; the copy does not establish that this increase was significant. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Inhibition of Idol with an antisense oligonucleotide reduces amyloid burden in an APP transgenic mouse model.

    “In addition, the inhibition of Idol with an antisense oligonucleotide was reported to reduce the amyloid burden in an APP transgenic mouse model. 62”

    From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [62]

  • Targeting 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 Gao et al 2020

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Plaque-size analysis names different stains

    Minor

    The results describe the plaque-size analysis as using the X34-stained data set, but the caption for the cited Fig. 2F describes Aβ-antibody-stained plaques.

  • Cued fear-conditioning tone duration differs

    Minor

    The results say the tone played for the last 3 minutes of the day-3 test, while the Fig. 5 caption says it played for the last 2 minutes.

  • ApoER2 increase is attributed to the wrong figure panel

    Minor

    The discussion cites Fig. 1C for increased ApoER2 levels, but its caption identifies Fig. 1C as ASO-localization staining. The protein analysis is identified as Fig. 1D.

3 of 3

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Related

Authors
Gao, J., Littman, R., Diamante, G., Xiao, X., Ahn, I. S., Yang, X., Cole, T. A., & Tontonoz, P.
Affiliations
  • The Ohio State University Wexner Medical Center (US)
  • University of California, Los Angeles (US)
  • Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California—Los Angeles, Los Angeles
  • Ionis Pharmaceuticals (United States) (US)
Corresponding author
  • Gao, Jie
  • Tontonoz, Peter
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2020-03-30
Volume
40
Issue
8
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.00518-19
PMC
PMC7108818
OpenAlex
W3002043434
Cited by
15
References
47
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1
FWCI
0.75
Type
journal article
Language
en
Open access
Licence
doi.org/10.1080/policies-text-data-mining (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
HHS | National Institutes of Health (R00 AG054736, HL136618)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
idols, E3 ubiquitin ligase, Alzheimer's disease, amyloidosis, amyloid-beta clearance, microglia, disease-associated microglia, LDL receptor, antisense oligonucleotides, APP/PS1 mice, spatial learning and memory, lysosomal genes, hippocampus, single-cell transcriptomics
MeSH terms
Alzheimer Disease, Amyloidosis, Animals, Apolipoproteins E, Brain, Cognition, Disease Models, Animal, Hippocampus, Male, Mice, Inbred C57BL, Mice, Transgenic, Receptors, LDL, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Oligodeoxyribonucleotides, Antisense, Ubiquitin-Protein Ligases, Mice

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 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

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Statistics and arithmetic are recomputed, not judged.

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