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Cited by 57Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease

Open access
Rajani, Rikesh M., Ellingford, Robert, Hellmuth, Mariam, Harris, Samuel S., Taso, Orjona S., Graykowski, David, Lam, Francesca Kar Wey, Arber, Charles +11 more·2024·PLOS Biology
DOI 10.1371/journal.pbio.3002727PMC PMC11265669

Published version of a preprint

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Abstract

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer’s disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.

AI snapshot

Written from the paper’s full text.

TL;DR

Oligodendrocytes express the machinery for amyloid beta (Aβ) production and produce Aβ in human tissue and iPSC models, challenging the assumption that neurons are the main pathogenic source. Selectively suppressing oligodendrocyte Aβ production in an AD knock-in mouse model reduces plaques modestly and rescues early neuronal hyperactivity.

Key findings

  • Across four public human snRNA-seq datasets, oligodendrocytes expressed high levels of APP, BACE1, and most γ-secretase components—often higher than other brain cell types, including neurons—except PSEN2; mouse proteomics and immunohistochemistry confirmed APP/BACE1 protein in oligodendrocytes.
  • In postmortem prefrontal cortex, approximately 80% of oligodendrocytes expressed both APP and BACE1 in controls and sporadic AD (sAD); sAD brains had more oligodendrocytes in Layers 5/6 and significantly more Aβ-capable oligodendrocytes (n = 4 control, n = 5 sAD).
  • Human iPSC-derived oligodendrocytes produced Aβ in a BACE1-dependent manner, produced more Aβ40 than neurons from the same fAD lines, had a higher Aβ42/Aβ40 ratio, and produced more soluble Aβ aggregates; aggregate lengths were similar (neurons 79.8 nm ± 58.7 nm; oligodendrocytes 77.7 nm ± 58.5 nm).
  • In AppNL-G-F mice, oligodendrocyte-specific BACE1 knockout reduced plaque number/area by approximately 25% across visual, retrosplenial, and motor cortex, whereas neuronal BACE1 knockout nearly eliminated plaques; oligodendrocyte knockout restored neuronal firing rates to WT levels (WT vs Oligo-KO: p > 0.9999), and oligodendrocyte-conditioned media containing soluble Aβ increased neuronal firing in WT mice.

Methods

  • Public human snRNA-seq datasets, mouse proteomics, RNAscope ISH on postmortem human prefrontal cortex, and human iPSC-derived oligodendrocytes, neurons, OPCs, astrocytes, and microglia; Aβ was measured by ELISA and soluble aggregates by single-molecule pull-down with DNA-PAINT super-resolution imaging.
  • AppNL-G-F knock-in mice with tamoxifen-inducible BACE1 knockout in oligodendrocytes (PLP1-Cre/ERT) or neurons (Thy1-Cre/ERT2), tamoxifen given at 4–8 weeks; plaque load assessed at 4 months, and Neuropixels recordings performed in awake 3-month-old mice or during acute media injection in WT mice.
  • Statistical comparisons used t tests, one-way ANOVA with post hoc tests, and Kruskal–Wallis with Dunn’s post hoc tests, as specified in figure legends.

Limitations

  • The paper does not state a dedicated limitations section.
  • Evident from the text: human postmortem analysis used small samples (n = 4 control, n = 5 sAD) and is cross-sectional; iPSC lines were limited, and fAD lines were considered together rather than compared because of rarity.
  • Evident from the text: the in vivo causal work is in the AppNL-G-F mouse model, plaque reduction after oligodendrocyte BACE1 knockout was modest (~25%), and functional rescue was assessed primarily in retrosplenial cortex; the authors note BACE inhibition concerns for neuronal substrates such as SEZ6, though they report SEZ6 is not expressed in oligodendrocytes.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pbio.3002727

Cites

89 of 90 references verified1 citation errors · 0 not checkable

Statistics

Claims the paper makes

52 of 70 cited sources checked · 26 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    At the protein level, oligodendrocytes contain high levels of APP, BACE1, and PSEN1.

    “we exploited publicly available proteomics data derived from isolated mouse brain cells [14] and found that, at the protein level, oligodendrocytes indeed contain high levels of APP, BACE1, and PSEN1 (S1 Fig).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] K Sharma, 2015, Cell type- and brain region-resolved mouse brain proteome, Nat Neurosci source
  • Findingown data

    Apart from PSEN2, oligodendrocytes had elevated expression of all genes involved in amyloid beta production in human single-nucleus RNA sequencing datasets.

    “We found that, apart from PSEN2 (which is not essential for gamma secretase function when PSEN1 is present [13]), oligodendrocytes had elevated expression of all of these genes (Fig 1A–1D).”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [5] H Mathys, 2019, Single-cell transcriptomic analysis of Alzheimer’s disease, Nature source

      The citation is attached to the parenthetical claim that PSEN2 is not essential for gamma-secretase function when PSEN1 is present; the oligodendrocyte-expression finding is presented as the citing authors’ own result. The cited paper’s Discussion and cell-type differential-expression section discuss oligodendrocyte transcriptional changes, but the passages retrieved for PSEN1, PSEN2, and gamma-secretase do not address that functional claim. No page numbers were available. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [10] Y Zhou, 2020, Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease, Nat Med source

      The citation is attached to the parenthetical claim that PSEN2 is not essential for gamma-secretase function when PSEN1 is present; the oligodendrocyte-expression finding is presented as the citing authors’ own result. Searches of our copy for PSEN2 and PSEN1 with gamma-secretase function found no passage addressing that claim. The Results and Discussion passages concern oligodendrocyte responses to amyloid pathology, not PSEN2’s necessity. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [11] TE Bakken, 2021, Comparative cellular analysis of motor cortex in human, marmoset and mouse, Nature source

      The citation is attached to the parenthetical claim that PSEN2 is not essential for gamma-secretase function when PSEN1 is present. Our copy’s Methods > SNARE–seq2 and Consensus M1 taxonomy across species passages discuss oligodendrocyte profiling, but do not address PSEN1, PSEN2, gamma-secretase function, or elevated expression of amyloid-beta-production genes. Searches for those terms found no decisive passage. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [12] BB Lake, 2018, Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain, Nat Biotechnol source

      The citation in the printed sentence is attached to the parenthetical claim that PSEN2 is not essential for gamma-secretase function when PSEN1 is present; the elevated-expression finding is presented as the citing authors’ own result. Our copy’s Results section discusses oligodendrocyte expression in remyelination, but the passages found when searching for PSEN2, PSEN1, gamma-secretase, and amyloid-beta production do not address that parenthetical claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Findingown data

    Amyloid beta production by human iPSC-derived oligodendrocytes was significantly reduced by administration of the BACE1 inhibitor NB-360.

    “and that this Aβ production was significantly reduced by administration of the BACE1 inhibitor NB-360 [20]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] U Neumann, 2015, A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice., Mol Neurodegener source

      The Results (Chronic NB-360 treatment in APP51/16 transgenic mice; page unavailable) report significant reductions in brain Aβ after NB-360 treatment. The Methods (In vitro protease and Aβ-release assays; page unavailable) describe experiments in Chinese hamster ovary cells expressing human APP, not human iPSC-derived oligodendrocytes. The source supports the inhibitor’s effect on Aβ, but not the claimed cell type. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Recent clinical trials demonstrate slowing of cognitive and functional decline in individuals with Alzheimer's disease treated with anti-amyloid beta antibodies.

    “Recent clinical trials demonstrating a slowing of cognitive and functional decline in individuals with AD treated with anti-Aβ antibodies indeed reinforce the important role of Aβ in AD pathophysiology [1,2].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [1] CH van Dyck, 2022, Lecanemab in Early Alzheimer’s Disease, N Engl J Med source
    • cites [2] JR Sims, 2023, Donanemab in Early Symptomatic Alzheimer Disease, JAMA source
  • Study design and conductcitation

    Tamoxifen administration between the ages of 4 and 8 weeks, after the majority of developmental myelination has taken place, avoids developmental and early postnatal effects of BACE1 knockout on myelin.

    “To avoid developmental and early postnatal effects of BACE1 knockout on myelin [34], we used tamoxifen inducible Cre lines, with tamoxifen administered between the ages of 4 and 8 weeks (after the majority of developmental myelination has taken place [35]), according to standard protocols [36].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [34] X Hu, 2006, Bace1 modulates myelination in the central and peripheral nervous system, Nat Neurosci source
    • cites [35] K Hamano, 1998, A quantitative study of the progress of myelination in the rat central nervous system, using the immunohistochemical method for proteolipid protein, Dev Brain Res source
    • cites [36] M-H Ou-Yang, 2018, Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice., Sci Transl Med. source
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 35
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Accumulation of amyloid beta is an early critical hallmark of Alzheimer's disease and an important target for understanding pathophysiology and therapy.

    “Accumulation of amyloid beta (Aβ) is an early critical hallmark of the disease and thus is an important target for understanding pathophysiology and therapy.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [1] CH van Dyck, 2022, Lecanemab in Early Alzheimer’s Disease, N Engl J Med source

      The Abstract says aggregated Aβ may initiate or potentiate pathological processes in Alzheimer’s disease, and the paper tests an Aβ-targeting therapy in people with early disease. It does not establish that Aβ accumulation is an early, critical hallmark; the claim states that significance more definitively than the source does. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [2] JR Sims, 2023, Donanemab in Early Symptomatic Alzheimer Disease, JAMA source

  • Classified as probably not a substantial claim.

    Premisecitation

    Transcriptomic studies have shown changes in microglia, astrocytes, and oligodendrocytes in human Alzheimer's disease tissue.

    “Recently, transcriptomic studies have shown changes not only in microglia and astrocytes but also in oligodendrocytes, the myelinating cells of the central nervous system, in both human AD tissue [5,6]”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [5] H Mathys, 2019, Single-cell transcriptomic analysis of Alzheimer’s disease, Nature source
    • cites [6] JS Sadick, 2022, Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease., Neuron source

      The Abstract and Introduction report transcriptomic changes in astrocytes and oligodendrocytes from human AD tissue. This paper does not report corresponding changes in microglia, so it supports only part of the claim attributed to the joint citation. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Transcriptomic studies have shown changes in microglia, astrocytes, and oligodendrocytes in mouse models of Alzheimer's disease.

    “and in mouse models of AD [7,8]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [7] WT Chen, 2020, Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease, Cell source
    • cites [8] H Park, 2023, Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice., Nat Commun. source

      The Results (no page available) report single-cell transcriptomic changes in oligodendrocytes from AD mouse models and analyze disease-associated microglia. The Introduction describes disease-associated astrocytes from another study, but the passages do not establish transcriptomic changes in astrocytes in mouse models. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The reduction in amyloid beta production by NB-360 in oligodendrocytes is similar to what has previously been shown in human iPSC-derived neurons upon administration of NB-360 or similar BACE inhibitors.

    “Notably, this reduction in Aβ production is similar to what has previously been shown in human iPSC-derived neurons upon administration of NB-360 or similar BACE inhibitors [21–24]”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [21] COY Hung, 2018, Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer’s Disease., Cell Rep source
    • cites [22] C Cusulin, 2019, Gamma secretase modulators and BACE inhibitors reduce Aβ production without altering gene expression in Alzheimer’s disease iPSC-derived neurons and mice, Mol Cell Neurosci source
    • cites [23] C Arber, 2021, Familial Alzheimer’s Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis., Cell Rep source

      The Results section on secretase inhibition reports treating iPSC-derived neural precursors with the BACE inhibitor LY2886721, but reports effects on proliferation and neurogenesis, not Aβ production. The Methods describe an Aβ42 assay without linking it to an inhibitor-induced reduction. Searches for NB-360 and reduced Aβ after BACE inhibition found no passage establishing the claimed neuronal result. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [24] S Moore, 2015, APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons., Cell Rep source

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

    Premisecitation

    Elevated levels of soluble amyloid beta have previously been reported in the white matter of individuals with Alzheimer's disease.

    “although elevated levels of soluble Aβ have previously been reported in the white matter of individuals with AD [49]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] LE Collins-Praino, 2014, Soluble amyloid beta levels are elevated in the white matter of Alzheimer’s patients, independent of cortical plaque severity, Acta Neuropathol Commun source

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

    Premisecitation

    The relationship between amyloid beta monomer concentration and aggregate concentration is nonlinear, so small changes in monomer can result in larger increases in the number of aggregates.

    “it is also worth noting that the relationship between Aβ monomer concentration and aggregate concentration is nonlinear, so small changes in monomer can result in larger increases in the number of aggregates [44]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] M Iljina, 2016, Quantitative analysis of co-oligomer formation by amyloid-beta peptide isoforms., Sci Rep source

  • May combine two claims.

    Premisecitation

    Most neuronal amyloid beta is secreted at presynaptic terminals, thus favouring plaque deposition in the grey matter.

    “The lower abundance of plaques in the white matter could further be explained by the evidence that most neuronal Aβ is secreted at presynaptic terminals, thus favouring plaque deposition in the grey matter [50,51].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [50] O Lazarov, 2002, Evidence that synaptically released β-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice, J Neurosci source

      The Abstract reports that Aβ released from presynaptic sites in the dentate gyrus is deposited in extracellular plaques. The Discussion calls synaptic release a principal contributor to deposition but acknowledges limits to that conclusion. The paper does not establish that most neuronal Aβ is secreted at presynaptic terminals or compare plaque deposition in grey and white matter; page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [51] JR Cirrito, 2005, Synaptic activity regulates interstitial fluid amyloid-β levels in vivo, Neuron source

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

    Premisecitation

    iPSC-derived microglial-like cells were generated using established protocols.

    “iPSC-derived microglial-like cells were generated using established protocols [64,65].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [64] P Garcia-Reitboeck, 2018, Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis, Cell Rep source
    • cites [65] X Xiang, 2018, The Trem2 R47H Alzheimer’s risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans., Mol Neurodegener. source

  • Classified as probably not a substantial claim.

    Premisecitation

    The failure of BACE inhibition trials to demonstrate beneficial effects is thought to be due to effects on other neuronal BACE substrates such as SEZ6.

    “which is thought to be due to the effects on other neuronal BACE substrates such as SEZ6 [54]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [54] K Zhu, 2018, Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6, Biol Psychiatry source

      The Discussion reports that disrupting SEZ6 function contributes to BACE1 inhibition-induced synaptic alterations in mice. The paper does not establish that this mechanism explains why BACE-inhibition trials failed to show clinical benefit; it says whether similar treatment deficits occur in humans remains unknown (introductory text indexed under Abstract; page unavailable). (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Human single nucleus RNA sequencing data from Bakken and colleagues were obtained from the Human Protein Atlas.

    “Human single nucleus RNA sequencing data from Bakken and colleagues [11] were obtained from the Human Protein Atlas (proteinatlas.org).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] TE Bakken, 2021, Comparative cellular analysis of motor cortex in human, marmoset and mouse, Nature source

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

    Premisecitation

    Human single nucleus RNA sequencing data from Mathys and colleagues and Lake and colleagues were obtained from The Myeloid Landscape 2 portal.

    “Human single nucleus RNA sequencing data from Mathys and colleagues [5] and Lake and colleagues [12] were obtained from The Myeloid Landscape 2 portal (http://research-pub.gene.com/BrainMyeloidLandscape) [70].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [5] H Mathys, 2019, Single-cell transcriptomic analysis of Alzheimer’s disease, Nature source
    • cites [12] BB Lake, 2018, Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain, Nat Biotechnol source
    • cites [70] K Srinivasan, 2020, Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation, Cell Rep source

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

    Premisecitation

    BACE1fl/fl mice were previously generated and provided by R.V.

    “BACE1fl/fl mice (C57BL/6-Bace1tm1.1mrl) were previously generated and provided by R.V. [36].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] M-H Ou-Yang, 2018, Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice., Sci Transl Med. source

      The Results section ('Generation and characterization of conditional BACE1 knockout mice'; page unavailable) states that BACE1fl/fl mice were generated, and Materials and Methods ('Animals'; page unavailable) describes how. R.V. is an author of the cited paper, but our copy does not say that he provided the mice to the citing researchers. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Oligodendrocytes were derived from iPSCs as previously described.

    “Oligodendrocytes were derived from iPSCs as previously described [17].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] M Ehrlich, 2017, Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors, Proc Natl Acad Sci source

  • May combine two claims.

    Premisecitation

    The technique used to quantify soluble Aβ aggregates has previously been validated in multiple studies and specifically detects aggregates, not monomers.

    “The technique used to quantify soluble aggregates has previously been validated in multiple studies and has been shown to specifically detect aggregates, and not monomers [29–31].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [29] Z Xia, 2023, A computational suite for the structural and functional characterization of amyloid aggregates, Cell Reports Methods source

      The Introduction (page unavailable) describes SiMPull as an established assay for counting soluble aggregates, and the Results and discussion report validation of the ACT analysis toolkit using Aβ aggregates. Our copy does not establish that the assay detects aggregates but not monomers, or document validation of that specificity across multiple studies. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [30] E Fertan, 2023, Cerebral organoids with chromosome 21 trisomy secrete Alzheimer’s disease-related soluble aggregates detectable by single-molecule-fluorescence and super-resolution microscopy, Mol Psychiatry source
    • cites [31] JSH Danial, 2022, Constructing a cost-efficient, high-throughput and high-quality single-molecule localization microscope for super-resolution imaging., Nat Protoc. source

      Figure 5 (p. 56) describes imaging recombinant α-synuclein aggregates, while the Introduction (p. 1) mentions amyloid aggregates generally. Our copy does not address validation of a technique for quantifying soluble Aβ aggregates or show that it detects aggregates rather than monomers; searches for those terms found no such passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The study used iPSC lines with APP V717I, PSEN1 R278I, PSEN1 int4del, and PSEN1 WT (corrected) mutations.

    “The following cell lines were used in this study: APP V717I 1 (APP V717I mutation), PSEN1 R278I (PSEN1 R278I mutation), PSEN1 int4del (intron 4 deletion in PSEN1), PSEN1 WT (PSEN1 int4del line CRISPR edited to correct the mutation [19]).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] C Arber, 2019, Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout., Brain Commun. source

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

    Premisecitation

    Protein expression data of isolated mouse brain cells was generated by Sharma and colleagues using MACS to isolate microglia, astrocytes, oligodendrocytes, and neurons from young (P8) C57/BL6 mice (3 biological replicates), analysed by mass spectrometry.

    “Protein expression data of isolated mouse brain cells was generated by Sharma and colleagues [14] using Magnetic-Activated Cell Sorting (MACS) to isolate microglia, astrocytes, oligodendrocytes, and neurons from the brains of young (P8) C57/BL6 mice (3 biological replicates), analysed by mass spectrometry.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] K Sharma, 2015, Cell type- and brain region-resolved mouse brain proteome, Nat Neurosci source

      The Results section, “Proteome analysis of acutely isolated CNS cell types” (page unavailable), confirms magnetic sorting of microglia, astrocytes, oligodendrocytes and PSA-NCAM+ neuronal progenitors from P8 mice, with three biological replicates and quantified proteins. The claim calls the fourth population neurons rather than neuronal progenitors. The Online Methods identify C57BL/6 mice for the separate P60 brain-region analysis but do not specify the strain of the P8 mice. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Human single nucleus RNA sequencing data from Zhou and colleagues were obtained via the AD Knowledge Portal.

    “Human single nucleus RNA sequencing data from Zhou and colleagues [10] were obtained via the AD Knowledge Portal (https://adknowledgeportal.org) study snRNAseqAD_TREM2.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Y Zhou, 2020, Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease, Nat Med source

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

    Premisecitation

    iPSCs were previously obtained or generated, and validated, by CA and SW.

    “iPSCs were previously obtained or generated, and validated, by CA and SW [18,19].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [18] C Arber, 2020, Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta, Mol Psychiatry source

      The Cell culture section (page not specified) describes generating iPSCs by reprogramming fibroblasts and screening newly generated lines by karyotype and G-band analysis. It does not identify CA and SW as the people who obtained, generated, or validated the cells. (LLM, conf=0.80)

      Experimental — accuracy not yet measured
    • cites [19] C Arber, 2019, Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout., Brain Commun. source

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

    Premisecitation

    iPSC-derived astrocytes were generated using an established protocol.

    “iPSC-derived astrocytes were generated using an established protocol [63].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] CE Hall, 2017, Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS., Cell Rep source

  • May combine two claims.

    Findingown data

    After 30 days of maturation, human iPSC-derived oligodendrocyte cultures contained 6.3% MBP+ oligodendrocytes and 87.3% oligodendrocyte precursor cells/pre-myelinating oligodendrocytes, but almost no other non-oligodendroglial cell types.

    “After 30 days of maturation, these cultures contained 6.3% MBP+ oligodendrocytes and 87.3% oligodendrocyte precursor cells (OPCs)/pre-myelinating oligodendrocytes, but almost no other non-oligodendroglial cell types (Figs 3A and S5A–S5C)”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Selectively suppressing oligodendrocyte amyloid beta production restores neuronal function in the mouse model in vivo.

    “and restores neuronal function in the mouse model in vivo”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neurons showed greater variability in APP and BACE1 expression levels, with a subset showing very high expression and others showing only minimal expression.

    “though neurons showed a greater variability in expression levels, with a subset of neurons showing very high expression yet others showing only minimal expression (S4C and S4D Fig).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Human oligodendrocytes can generate amyloid beta in greater amounts and with a higher proportion as soluble aggregates compared to neurons.

    “we have shown that human oligodendrocytes not only produce Aβ, but they can also generate Aβ in greater amounts and with a higher proportion as soluble aggregates compared to neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The greater amyloid beta production and higher proportion as soluble aggregates in oligodendrocytes was seen both with and without familial Alzheimer's disease mutations.

    “This was seen in oligodendrocytes both with and without fAD mutations.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Mature cortical neurons begin to appear from 60 days after final plating.

    “Mature cortical neurons begin to appear from 60 days after final plating”
    Quote in the paperNot a substantial claim

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

    Findingown data

    35 days after glial induction, almost all cells were oligodendroglia (OLIG2+ and/or MBP+) and cells with mature MBP+ sheets were visible.

    “35 days after glial induction, almost all cells were oligodendroglia (OLIG2+ and/or MBP+) and cells with mature MBP+ sheets were visible.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingnone given

    AD tissue is from donors with a clinical diagnosis of sporadic AD and a high level of AD pathological change (A3, B3, C2, or C3).

    “AD tissue is from donors with a clinical diagnosis of sporadic AD and a high level of AD pathological change (A3, B3, C2, or C3).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingnone given

    Control tissue is from donors with no clinical diagnosis of neurological disease and no or minimal AD-related pathology.

    “Control tissue is from donors with no clinical diagnosis of neurological disease and no or minimal AD-related pathology.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Genetic risk associated with Alzheimer's disease is enriched in age-dependent transcriptome networks of both microglia and oligodendrocytes.

    “In addition, genetic risk associated with AD is enriched in age-dependent transcriptome networks of both microglia and oligodendrocytes [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] AC Graham, 2023, Genetic variation associated with human longevity and Alzheimer’s disease risk act through microglia and oligodendrocyte cross-talk., medRxiv. source

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

    Premisecitation

    Among the earliest responses of neurons to amyloid beta accumulation is an abnormal increase in excitability.

    “Among the earliest responses of neurons to this accumulation of Aβ is an abnormal increase in excitability [3,4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] MA Busche, 2008, Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer’s Disease, Science (80-). source
    • cites [4] J Giorgio, 2024, Article Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation, Neuron source

  • May combine two claims.

    Interpretationown data

    The observed increase in the number of amyloid-beta-capable oligodendrocytes in sporadic Alzheimer's disease brains suggests that oligodendrocyte amyloid beta production may play an important but hitherto unappreciated role in the pathogenesis of the disease.

    “The observed increase in the number of Aβ-capable oligodendrocytes in sAD brains suggests that oligodendrocyte Aβ production may play an important, but hitherto unappreciated, role in the pathogenesis of the disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AppNL-G-F knock-in mice express App under its endogenous promoter in a physiological manner with regards to both cell type and amount, and avoid the issue of APP overexpression and abnormal expression patterns.

    “We elected to use the AppNL-G-F knock-in mouse model for this study as it expresses App under its endogenous promoter in a physiological manner with regards to both cell type and amount, and avoids the issue of APP overexpression and abnormal expression patterns.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] T Saito, 2014, Single App knock-in mouse models of Alzheimer’s disease, Nat Neurosci source

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

    Premisecitation

    Recent anti-amyloid beta antibody therapies targeting plaques have been shown to be effective in slowing the clinical course of Alzheimer's disease.

    “While recent anti-Aβ antibody therapies targeting plaques have been shown to be effective in slowing the clinical course of AD”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] WK Self, 2023, Emerging diagnostics and therapeutics for Alzheimer disease, Nat Med source

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

    Study design and conductnone given

    For oligodendrocyte analysis, cells were quantified manually after blinding the experimenter to animal genotype.

    “For oligodendrocyte analysis, sections were imaged using a Zeiss LSM 800 confocal microscope using a 40× magnification (field of view (FOV): 159.73 × 159.73 μm; 2,101 × 2,101 pixels), 4 to 6 FOV from Layers 5/6 of the cortex were captured across 2 to 3 sections, and cells were quantified manually using the FIJI build of ImageJ (open source) after blinding the experimenter to animal genotype.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    The clustering analysis requires close proximity of at least two dimers, ensuring that detected species are aggregates.

    “The clustering analysis used requires close proximity of at least 2 of these dimers, thus further ensuring that what are detected are aggregates.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    RNAscope quantification was performed after blinding the experimenter to donor ID and diagnosis.

    “The number of cells expressing different genes was quantified manually using the FIJI build of ImageJ software (open source) after blinding of the experimenter to the donor ID and diagnosis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Imaging and analysis was performed blind to genotype/condition in the oligodendrocyte autophagy analysis.

    “Cells were segmented based on Olig2 staining, the nuclear mask was dilated to capture the cytoplasm, and the fluorescent intensity normalised to surface was measured. Imaging and analysis was performed blind to genotype/condition.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study was carried out in accordance with the Declaration of Helsinki.

    “The study was carried out in accordance with the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Imaging and analysis was performed blind to genotype/condition in the myelin sheath analysis.

    “Only complete myelin sheaths that started and ended within the 30-μm section were traced and measured, and 120 sheaths were measured per mouse. Imaging and analysis was performed blind to genotype/condition.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    n values stated refer to true biological replicates.

    “n values stated refer to true biological replicates—depending on the experiment an individual n is a human brain (comprising 5 FOV imaged), a cell line (comprising 1 to 4 independent inductions, each of which is the average of 2 to 5 wells), a mouse (comprising 2 to 3 whole sagittal sections imaged or 3 to 12 FOV), or a neuron/unit.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Statistical tests were chosen for each experiment based on the normality of data and sample matching.

    “Statistical tests were chosen for each experiment based on the normality of data and sample matching.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All experimental procedures were conducted in accordance with the Animal (Scientific procedures) Act 1986, approved by the Animal Welfare and Ethical Review Body at University College London (UCL), and performed under an approved UK Home Office project licence at UCL (PP8718352 to MAB).

    “All experimental procedures were conducted in accordance with the Animal (Scientific procedures) Act 1986, approved by the Animal Welfare and Ethical Review Body at University College London (UCL), and performed under an approved UK Home Office project licence at UCL (PP8718352 to MAB).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    AppNL-G-F mice were provided by the RIKEN BRC through the National BioResource Project of the MEXT, Japan.

    “AppNL-G-F mice [C57BL/6-App<tm3(NL-G-F)Tcs> (No.RBRC06344)] were provided by the RIKEN BRC through the National BioResource Project of the MEXT, Japan [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] T Saito, 2014, Single App knock-in mouse models of Alzheimer’s disease, Nat Neurosci source

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

    Premisereasoning

    The single-molecule pull-down method allows quantification of stable assemblies or aggregates at picomolar concentrations, with higher sensitivity than bulk biochemical methods.

    “This method allows quantification of stable assemblies or aggregates at picomolar concentrations, which is a much higher sensitivity than bulk biochemical methods.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Cortical neurons were derived from iPSCs as previously described.

    “Cortical neurons were derived from iPSCs as previously described [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Y Shi, 2012, Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks, Nat Protoc source
45 of 45

  • The authors state this as an assumption.

    Neurons are the primary source of pathogenic amyloid beta in the brain.

    “the traditional assumption that neurons are the primary source of pathogenic Aβ in the brain has remained untested”
1 of 1

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(2, 10) = 11.23reported p = .0028 · recomputed p = .003

    “F(2,10) = 11.23, p = .0028”

1 of 1

Self-check

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

Self-check results appear here once an independent check has confirmed them.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. JR Sims, 2023, Donanemab in Early Symptomatic Alzheimer Disease, JAMA, 46285, 1

Cited by

Sorted by citations

Related

Authors
Rajani, R. M., Ellingford, R., Hellmuth, M., Harris, S. S., Taso, O. S., Graykowski, D., Lam, F. K. W., Arber, C., Fertan, E., Danial, J. S. H., Swire, M., Lloyd, M., Giovannucci, T. A., Bourdenx, M., Klenerman, D., Vassar, R., Wray, S., Sala Frigerio, C., & Busche, M. A.
Affiliations
  • UK Dementia Research Institute (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • University of Cambridge (GB)
  • University of St Andrews (GB)
  • University College London (GB)
  • Northwestern University (US)
Corresponding author
Busche, Marc Aurel
ORCID
Venue
PLOS Biology
Publisher
Public Library of Science (PLoS)
Published
2024-07-23
Volume
22
Issue
7
Pages
e3002727
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.3002727
PMC
PMC11265669
OpenAlex
W4400906342
Cited by
57
References
87
Citations by year
2026: 22 · 2025: 27 · 2024: 8
FWCI
13.62
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • St Andrews Research Repository (St Andrews Research Repository) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • UK Dementia Research Institute
  • Medical Research Council (MR/X011038/1, MR/X019977/1)
  • National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/W001675/1)
  • Alzheimer's Association (AARF-23 1149637)
  • National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre
  • Alzheimer’s Association (23AARFD-1029918)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloid-beta, oligodendrocytes, neuronal hyperactivity, amyloid-beta production, therapeutic target, neuropathology, neuronal dysfunction
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Neurons, Oligodendroglia, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Gene Knock-In Techniques

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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