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Cited by 16Bone Metabolism and DiseasesTelomeres, Telomerase, and SenescenceAmyloidosis: Diagnosis, Treatment, Outcomes

Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis

Open access
Kumar, Surendra, Song, Kangping, Wang, Jiekang, Baghel, Meghraj Singh, Zeng, Yixiang, Shen, Ke, Zheng, Junying, Crane, Janet +7 more·2025·Nature Aging
DOI 10.1038/s43587-025-00924-zPMC PMC12443615

Published version of a preprint

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Abstract

SUMMARY The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on the aging process of these organs. Here, we demonstrate that both transgenic mice modeling Alzheimer’s disease (AD) and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits surrounding the BMAds. Senescent BMAds acquire a secretory phenotype, resulting in a marked increase in the secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and is sufficient to promote the formation of insoluble amyloid deposits from soluble Aβ peptides in in vitro and ex vivo 3D BMAd-based culture experiments. Additionally, Combined treatment with SAP/PTX2 and Aβ peptides promotes osteoclastogenesis but inhibits osteoblastogenesis of the precursor cells. Transplantation of senescent BMAds into the bone marrow cavity of healthy young mice is sufficient to induce bone loss. Finally, pharmacological depletion of SAP/PTX2 from aged mice abolishes bone marrow amyloid deposition and effectively rescues the low bone mass phenotype. Thus, senescent BMAds, through the secretion of SAP/PTX2, contribute to the age-associated development of skeletal amyloidosis and resultant bone deficits.

AI snapshot

Written from the paper’s full text.

TL;DR

Senescent bone marrow adipocytes accumulate in Alzheimer’s disease and aged mice, secrete SAP/PTX2, and drive insoluble amyloid-β deposition around them, contributing to bone loss. Depleting SAP with CPHPC or eliminating senescent cells with dasatinib/quercetin reduces marrow amyloid and rescues bone mass.

Key findings

  • APP-PS1 mice at 9 months and 5xFAD mice at 13 months show low bone mass, increased marrow adiposity, senescent BMAds, and Aβ/amyloid deposits around BMAds; naturally aged mice at 22–24 months show similar marrow Aβ/amyloid accumulation. In AD BMAd conditioned medium, 17 of 111 adipokines/cytokines/growth factors were increased, with SAP/PTX2 the highest.
  • BMAd senescence involves CEBPα-activated p19Arf: ChIP showed CEBPα enrichment at all four p19Arf promoter sites in AD and old BMAds, but not at the p16Ink4a promoter.
  • Transplanting AD versus WT BMAds into young WT mice induced bone loss; transplanting old versus young BMAds induced bone loss that was reversed by dasatinib/quercetin. In vitro, combined SAP/PTX2 and Aβ promoted osteoclastogenesis and inhibited osteoblastogenesis; 3D BMAd cultures from AD/old mice formed Congo red– and ThioS-positive deposits with Aβ1–40.
  • In 18-month-old mice, 6 weeks of CPHPC reduced SAP by 58.5% in serum and 95% in bone marrow, abolished marrow amyloid deposits, increased BV/TV, Tb.Th, Ct.Ar and Ct.Th, decreased Tb.Sp, increased OCN+ osteoblasts, and reduced TRAP+ osteoclasts.

Methods

  • Male and female C57BL/6J, APP-PS1 and 5xFAD mice were used at 4, 9, 18, 22 and 24 months. CPHPC was given at 5 mg ml−1 in drinking water for 42 days; dasatinib/quercetin was given at 5 mg per kg and 50 mg per kg, respectively.
  • Bone phenotype and marrow adiposity were assessed by µCT, OsO4 staining, histology, immunofluorescence, RNAscope, ELISA for Aβ and SAP/PTX2, RT–qPCR, ChIP–qPCR, BMAd isolation/culture, cytokine arrays, intrafemoral BMAd transplantation, filter retention assays, 3D Matrigel BMAd cultures, and osteoblast/osteoclast differentiation assays.
  • Statistics used unpaired two-tailed Student’s t-tests and one-way or two-way ANOVA; n denotes biological replicates, with n ≥ 3 per group and data shown as mean ± s.e.m.

Limitations

  • The paper states that sample size was not predetermined, data collection and analysis were unblinded to mouse age, and CPHPC was developed based on human SAP and primarily tested in humans, although it was effective in mice.
  • The paper states uncertainty about the source of human Aβ in AD mouse bone marrow: hAPP transgene was not detected in flushed marrow cells, and nerve fibers or circulating Aβ are proposed sources; further co-immunostaining for hAPP and neuronal markers is needed.
  • The paper notes open questions about whether p16Ink4a and p19Arf are activated simultaneously or sequentially, whether cBMAds at other sites and other adipose depots show SAP secretion/amyloid deposition, and whether CPHPC improves bone in other pathological settings. Evident from the text: all reported skeletal amyloidosis and treatment findings are in mouse models, with no human bone data.

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

Integrity signals

Registry

Crossref · 10.1038/s43587-025-00924-z

Cites

115 of 115 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

37 of 63 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Interpretationreasoning

    AD mice at a younger age recapitulate an aged skeletal phenotype.

    “As aging-related osteoporosis typically features low bone mass, microarchitectural alterations and bone marrow adipose tissue expansion40–42, our findings suggest that AD mice at a younger age recapitulate an aged skeletal phenotype.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [40] Ali, D., Tencerova, M., Figeac, F., Kassem, M. & Jafari, A. The pathophysiology of osteoporosis in obesity and type 2 diabetes in aging women and men: the mechanisms and roles of increased bone marrow adiposity. Front. Endocrinol. 13, 981487 (2022). source
    • cites [41] Armas, L. A. & Recker, R. R. Pathophysiology of osteoporosis: new mechanistic insights. Endocrinol. Metab. Clin. North Am. 41, 475–486 (2012). source
    • cites [42] Paranthaman, M., Angu Bala Ganesh, K. S. V. & Silambanan, S. Linking bone marrow fat with decreased bone mineral density among Indian patients with osteoporotic fracture. Bioinformation 20, 49–54 (2024). source
  • Findingown data

    Increased H2AX+ signals overlap with p19+ signal around BMAds in both AD mice and old mice.

    “Additionally, we observed increased H2AX+ signals, indicative of reactive oxygen species generation, DNA damage and repair48,49. The increased H2AX+ signals overlapped with p19+ signal around BMAds in both AD mice (Fig. 3i,k) and old mice (Fig. 3l,n).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [48] Kang, M. A., So, E. Y., Simons, A. L., Spitz, D. R. & Ouchi, T. DNA damage induces reactive oxygen species generation through the H2AX–Nox1/Rac1 pathway. Cell Death Dis. 3, e249 (2012). source

      The Results section reports H2AX responses to DNA damage and ROS in cultured human cell lines, but does not address p19 signals, bone marrow adipocytes (BMAds), AD mice, or old mice. The overlap described in the quoted claim is presented as the citing authors’ own observation, not as a finding from this source. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [49] Katsuta, E. et al. H2AX mRNA expression reflects DNA repair, cell proliferation, metastasis, and worse survival in breast cancer. Am. J. Cancer Res. 12, 793–804 (2022).

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

  • Findingcitation

    The majority of the elevated factors in this context differ from the SASP factors previously identified in glucocorticoid-induced senescent BMAds.

    “It is noteworthy that the majority of the elevated factors in this context differ from the SASP factors previously identified in glucocorticoid-induced senescent BMAds47.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [47] Liu, X. et al. Oxylipin–PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow. Cell Metab. 35, 667–684 (2023). source
  • Findingown data

    γH2AX+ BMAds are substantially increased in both AD mice and old mice compared to their respective controls.

    “Immunofluorescence using the DNA damage marker γH2AX, a robust marker of senescent cells50–52, also revealed a substantial increase in γH2AX+ BMAds in both AD mice (Fig. 3q,r) and old mice (Fig. 3s,t) compared with their respective controls.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [50] Aquino-Martinez, R. et al. LPS-induced premature osteocyte senescence: implications in inflammatory alveolar bone loss and periodontal disease pathogenesis. Bone 132, 115220 (2020). source

      The citation is attached to the description of γH2AX as a marker, not to the citing paper’s reported increase in γH2AX+ BMAds. The Results section identifies γH2AX as a recognized marker of DNA damage and examines it alongside senescence markers in osteocytes, but does not establish it as a robust marker of senescent cells. It does not report the AD- or old-mouse BMAd comparisons. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [51] Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017). source

      The citation is attached to the description of γH2AX as a robust marker of senescent cells, not to the citing authors’ reported increase in γH2AX+ BMAds. The cited paper discusses DNA damage and senescence in its main text and measures other senescence markers (Online Methods, SADS analysis), but searches for γH2AX and bone marrow adipocytes found no passage validating that marker or reporting the stated comparison in AD and old mice. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [52] Farr, J. N. et al. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31, 1920–1929 (2016). source

      The citation is attached to the description of γH2AX as a senescence marker, not to the citing authors’ BMAd results. The Introduction describes persistent DNA damage as a feature of senescent cells, but our copy does not identify γH2AX as a robust marker. Its Results concern aging osteocytes, not γH2AX-positive BMAds in AD mice. (LLM, conf=0.80)

      Experimental — accuracy not yet measured
  • Findingown data

    5xFAD mice display a similar bone loss phenotype.

    “A similar bone loss phenotype was observed in 5xFAD mice (Fig. 1i–l), another widely used AD transgenic mouse model38,39.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [38] Hong, J. H. et al. Global changes of phospholipids identified by MALDI imaging mass spectrometry in a mouse model of Alzheimer’s disease. J. Lipid Res. 57, 36–45 (2016). source
    • cites [39] Oakley, H. et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006). source
  • Classified as probably not a substantial claim. 24
  • May combine two claims. 51

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

    Premisecitation

    Reduced bone mineral density traits are exhibited in various transgenic mouse models designed to mimic humanized AD neuropathology.

    “Similar to this clinical comorbidity, reduced bone mineral density traits are exhibited in various transgenic mouse models designed to mimic humanized AD neuropathology30,31.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [30] Dengler-Crish, C. M., Ball, H. C., Lin, L., Novak, K. M. & Cooper, L. N. Evidence of Wnt/β-catenin alterations in brain and bone of a tauopathy mouse model of Alzheimer’s disease. Neurobiol. Aging 67, 148–158 (2018). source
    • cites [31] Dengler-Crish, C. M., Smith, M. A. & Wilson, G. N. Early evidence of low bone density and decreased serotonergic synthesis in the dorsal raphe of a tauopathy model of Alzheimer’s disease. J. Alzheimers Dis. 55, 1605–1619 (2017). source

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

    Premisecitation

    Previous studies have shown abundant APP protein expression in bone and bone marrow cells, such as macrophages, osteoclasts and osteoblasts in WT mice.

    “Previous studies have shown abundant APP protein expression in bone and bone marrow cells, such as macrophages, osteoclasts and osteoblasts in WT mice79,80.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [79] Pan, J. X. et al. APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress. Cell Death Dis. 9, 1077 (2018). source

      The Results section (‘Osteoporotic deficits in APP−/− mice’; page unavailable) reports APP detection in mouse bone-marrow cells, including BMSCs and BMMs, and the Discussion reports higher APP levels in osteoblasts than in BMSCs. The paper examines osteoclasts, but the passages found do not establish abundant APP protein expression in osteoclasts specifically. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [80] Cui, S. et al. APPswe/Aβ regulation of osteoclast activation and RAGE expression in an age-dependent manner. J. Bone Miner. Res. 26, 1084–1098 (2011). source

      The Results section (“Age-dependent regulation of OC activation and bone mass in Tg2576 mice”; page unavailable) reports APP expression in bone marrow macrophages and osteoclasts derived from wild-type mice. It does not establish APP protein expression in osteoblasts, so the full list of cell types is not supported by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    PPARγ is a key transcription factor mediating p16Ink4a gene activation and BMAd senescence.

    “Previous studies revealed that PPARγ is a key transcription factor mediating p16Ink4a gene activation53 and BMAd senescence47.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [53] Gan, Q. et al. PPARγ accelerates cellular senescence by inducing p16INK4α expression in human diploid fibroblasts. J. Cell Sci. 121, 2235–2245 (2008). source
    • cites [47] Liu, X. et al. Oxylipin–PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow. Cell Metab. 35, 667–684 (2023). source

  • May combine two claims.

    Premisecitation

    CPHPC efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body.

    “This compound efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body24,62–68.”
    Quote in the paperSubstantial claim5 of 8 sources checked
    • cites [24] Pilling, D. & Gomer, R. H. The development of serum amyloid P as a possible therapeutic. Front. Immunol. 9, 2328 (2018). source

      In “Removing stuck SAP as a possible therapeutic for amyloidosis” (page unavailable), the paper says a small molecule causes two human SAP pentamers to bind together, after which the complex is quickly cleared from circulation; it also reports reduced serum SAP in mice. It does not identify the compound as CPHPC or say that it dissociates SAP already bound to amyloid deposits, so those parts of the claim are unsupported by our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [62] Klotz, S. A. & Lipke, P. N. The paradoxical effects of serum amyloid-P component on disseminated candidiasis. Pathogens 11, 1304 (2022). source
    • cites [63] Pepys, M. B. The pentraxins 1975–2018: serendipity, diagnostics and drugs. Front. Immunol. 9, 2382 (2018). source

      In “SAP and amyloidosis,” the paper says CPHPC forms a stable complex with SAP and rapidly depletes circulating SAP through liver clearance of that complex. It also says circulating SAP depletion removes much, but never all, SAP bound to amyloid deposits; complete elution requires a CPHPC concentration unattainable in vivo. The claim overstates dissociation from amyloid and presents it as the step leading to systemic depletion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [64] Pepys, M. B. et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417, 254–259 (2002). source
    • cites [65] Klotz, S. A., Sobonya, R. E., Lipke, P. N. & Garcia-Sherman, M. C. Serum amyloid P component and systemic fungal infection: does it protect the host or is it a Trojan horse? Open Forum Infect. Dis. 3, ofw166 (2016). source

      The SERUM AMYLOID P COMPONENT section (page unavailable) says that depleting SAP in plasma leads to its dissociation from amyloid deposits. It does not mention CPHPC or establish that the compound binds SAP; it also describes depletion as preceding dissociation, rather than following it. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [66] Gilchrist, K. B., Garcia, M. C., Sobonya, R., Lipke, P. N. & Klotz, S. A. New features of invasive candidiasis in humans: amyloid formation by fungi and deposition of serum amyloid P component by the host. J. Infect. Dis. 206, 1473–1478 (2012). source

      The Results and Discussion report SAP binding to fungal amyloid, but do not address CPHPC. Searches for CPHPC, SAP dissociation and SAP depletion found no passage describing the compound’s claimed effects. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [67] Pepys, M. B. Serum amyloid P component (not serum amyloid protein). Nat. Med. 5, 852–853 (1999). source
    • cites [68] Pepys, M. B., Dyck, R. F., de Beer, F. C., Skinner, M. & Cohen, A. S. Binding of serum amyloid P-component (SAP) by amyloid fibrils. Clin. Exp. Immunol. 38, 284–293 (1979).

  • May combine two claims.

    Interpretationreasoning

    BMAds are more susceptible or rapidly acquire a senescence phenotype compared to other cell types in the bone and/or bone marrow, likely because the master regulators of adipogenesis such as PPARγ and CEBPα also function as senescence gene activators.

    “Nevertheless, findings from the present study and our recent work on glucocorticoid-induced BMAds69 collectively suggest that BMAds are more susceptible or rapidly acquire a senescence phenotype compared to other cell types in the bone and/or bone marrow, likely because the master regulators of adipogenesis such as PPARγ and CEBPα also function as senescence gene activators.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [69] Liu, X. et al. Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis. Nat. Commun. 12, 1832 (2021). source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Osteoblasts are among the major cell types known to undergo cellular senescence during aging.

    “Osteoblasts are among the major cell types known to undergo cellular senescence during aging52,60.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [52] Farr, J. N. et al. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31, 1920–1929 (2016). source
    • cites [60] Khosla, S., Farr, J. N., Tchkonia, T. & Kirkland, J. L. The role of cellular senescence in ageing and endocrine disease. Nat. Rev. Endocrinol. 16, 263–275 (2020). source

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

    Premisecitation

    SAP/PTX2 is primarily produced in the liver in physiological conditions in humans.

    “Previous studies have shown that SAP/PTX2 is primarily produced in the liver in physiological conditions in humans81–83.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [81] Pilling, D., Cox, N., Thomson, M. A., Karhadkar, T. R. & Gomer, R. H. Serum amyloid P and a dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin ligand inhibit high-fat diet-induced adipose tissue and liver inflammation and steatosis in mice. Am. J. Pathol. 189, 2400–2413 (2019). source

      The introductory passage identifies SAP as PTX2 and discusses its plasma levels in patients, while the section on brown fat and liver examines liver inflammation and steatosis in mice. Neither states where SAP is primarily produced in healthy humans. Searches for liver production, hepatocyte synthesis, and physiological conditions found no passage addressing that point; page numbers were unavailable in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [82] Hutchinson, W. L., Hohenester, E. & Pepys, M. B. Human serum amyloid P component is a single uncomplexed pentamer in whole serum. Mol. Med. 6, 482–493 (2000). source

      The Introduction describes human SAP as a normal plasma glycoprotein, and the methods examine SAP in human serum. Neither those passages nor searches for liver, hepatic synthesis, and hepatocytes address where SAP is produced or whether the liver is its primary source under physiological conditions. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [83] Iwanaga, T. et al. Liver-specific and high-level expression of human serum amyloid P component gene in transgenic mice. Dev. Genet. 10, 365–371 (1989). source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    CPHPC (miridesap) at a concentration of 5 mg ml−1 in drinking water is an established dose for SAP depletion from the body.

    “To examine the effects of CPHPC on age-associated bone changes, male and female mice aged 18 months were treated with CPHPC (miridesap) at a concentration of 5 mg ml−1 in drinking water, which is an established dose for SAP depletion from the body62–65,67,68,84.”
    Quote in the paperSubstantial claim3 of 7 sources checked
    • cites [62] Klotz, S. A. & Lipke, P. N. The paradoxical effects of serum amyloid-P component on disseminated candidiasis. Pathogens 11, 1304 (2022). source
    • cites [63] Pepys, M. B. The pentraxins 1975–2018: serendipity, diagnostics and drugs. Front. Immunol. 9, 2382 (2018). source

      The “SAP and amyloidosis” section reports that CPHPC depletes circulating SAP in humans and describes SAP depletion with CPHPC in transgenic mice. The “Functions of human serum amyloid P component” section also reports sustained depletion during treatment. Neither section specifies 5 mg ml−1 in drinking water or establishes that concentration as a dose for mice; page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [64] Pepys, M. B. et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417, 254–259 (2002). source
    • cites [65] Klotz, S. A., Sobonya, R. E., Lipke, P. N. & Garcia-Sherman, M. C. Serum amyloid P component and systemic fungal infection: does it protect the host or is it a Trojan horse? Open Forum Infect. Dis. 3, ofw166 (2016). source

      The SERUM AMYLOID P COMPONENT section says that depleting plasma SAP is an effective treatment for amyloidoses. It does not mention CPHPC (miridesap), administration in drinking water, or a 5 mg ml−1 dose, so it does not establish the specific dosing claim. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [67] Pepys, M. B. Serum amyloid P component (not serum amyloid protein). Nat. Med. 5, 852–853 (1999). source
    • cites [68] Pepys, M. B., Dyck, R. F., de Beer, F. C., Skinner, M. & Cohen, A. S. Binding of serum amyloid P-component (SAP) by amyloid fibrils. Clin. Exp. Immunol. 38, 284–293 (1979).
    • cites [84] Pepys, M. B. et al. Amyloid P component. A critical review. Amyloid 4, 274–295 (1997). source

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

    Premisecitation

    Several recent studies have reported that CPHPC is also effective in depleting SAP in mice in different disease models.

    “However, consistent with our results in mice, several recent studies have reported that this drug is also effective in depleting SAP in mice in different disease models62,64.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [62] Klotz, S. A. & Lipke, P. N. The paradoxical effects of serum amyloid-P component on disseminated candidiasis. Pathogens 11, 1304 (2022). source
    • cites [64] Pepys, M. B. et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417, 254–259 (2002). source

  • May combine two claims.

    Findingcitation

    CPHPC efficiently reduces SAP concentration in serum (58.5% reduction) and bone marrow (95% reduction) in aged mice.

    “Our data demonstrated that CPHPC (miridesap), developed by Pepys’ team at University College London90–92, efficiently reduces SAP concentration in serum (58.5% reduction) and bone marrow (95% reduction) in aged mice.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [90] Schmidt, A. F. et al. Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders. Open Biol. 14, 230419 (2024). source

      The Discussion (page unavailable) identifies CPHPC as miridesap and reports effective SAP depletion, including a reduction of more than 95% in plasma while the drug is administered. It does not report a 58.5% serum reduction or a 95% bone-marrow reduction in aged mice; those figures are presented as the citing authors’ own data. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [91] Richards, D. B. et al. Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis. Sci. Transl. Med. 10, eaan3128 (2018). source
    • cites [92] Sahota, T. et al. Target mediated drug disposition model of CPHPC in patients with systemic amyloidosis. CPT Pharmacometrics Syst. Pharmacol. 4, e15 (2015). source

      The citation is attached to the description of CPHPC as developed by Pepys’ team, not to the aged-mouse reductions, which the citing authors present as their own data. The Abstract identifies CPHPC as a SAP-depleting drug, and Methods > Previous studies to support model development and evaluation links earlier CPHPC studies to M.B. Pepys (page unavailable). Our copy does not establish that his team developed the drug at University College London. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

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

    Premisecitation

    rBMAds and cBMAds have developmental and regulatory differences as well as distinct roles in hematopoiesis and bone remodeling.

    “Given the developmental and regulatory differences between rBMAds and cBMAds as well as their distinct roles in hematopoiesis and bone remodeling61, it would be valuable to further investigate whether cBMAds in other locations, such as tail vertebrae, exhibit a similar age-related phenotype.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [61] Scheller, E. L. et al. Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. Nat. Commun. 6, 7808 (2015). source

      The Results (Strain-specific MAT development in mice) and Discussion describe distinct developmental patterns and regulatory responses for rMAT and cMAT. But the Discussion says their functions must be clarified; it proposes that rMAT is better positioned to influence haematopoiesis or skeletal remodelling, rather than establishing distinct roles for both populations. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Study design and conductcitation

    Tail biopsy samples were used to isolate DNA to confirm the genotype of the strain using previously established primers by PCR.

    “Tail biopsy samples were used to isolate DNA to confirm the genotype of the strain using previously established primers by PCR93–95.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [93] Li, T. et al. The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model. Nat. Commun. 7, 12082 (2016). source

      The Methods section on generation of transgenic mice describes the mouse lines and their crossbreeding, but does not describe how their genotypes were confirmed. Searches for tail-biopsy DNA, PCR genotyping, and primers found no passage establishing the procedure attributed to this paper; page numbers were unavailable in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [94] LaClair, K. D. et al. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol. Neurodegener. 8, 18 (2013). source

      The Methods > Animals section identifies the APPswe/PS1ΔE9 mice used, but does not describe how their genotype was confirmed. Searches for tail-biopsy DNA, PCR genotyping, and primers found no passage describing the claimed procedure; the mention of marked tails in Methods > Fear conditioning concerns behavioral testing, not biopsy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [95] Naruse, S. et al. Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21, 1213–1221 (1998). source

      The Results describe cultures from embryos with different PS1 genotypes, but do not say how those genotypes were determined. Searches for tail biopsy, DNA isolation, PCR, and genotyping primers found no passage describing the claimed procedure. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The binding of SAP stabilizes amyloid fibrils and promotes their formation in the brain, thereby contributing to the pathogenesis of AD and cerebral amyloid angiopathy.

    “The binding of SAP stabilizes amyloid fibrils85 and promotes their formation in the brain86,87, thereby contributing to the pathogenesis of AD and cerebral amyloid angiopathy88,89.”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [85] Tennent, G. A., Lovat, L. B. & Pepys, M. B. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis. Proc. Natl Acad. Sci. USA 92, 4299–4303 (1995). source
    • cites [86] Mold, M., Shrive, A. K. & Exley, C. Serum amyloid P component accelerates the formation and enhances the stability of amyloid fibrils in a physiologically significant under-saturated solution of amyloid-β42. J. Alzheimers Dis. 29, 875–881 (2012). source
    • cites [87] Hamazaki, H. Amyloid P component promotes aggregation of Alzheimer’s β-amyloid peptide. Biochem. Biophys. Res. Commun. 211, 349–353 (1995). source
    • cites [88] Botto, M. et al. Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene. Nat. Med. 3, 855–859 (1997). source
    • cites [89] Al-Shawi, R. et al. Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo. Open Biol. 6, 150202 (2016). source

      The Background says SAP promotes fibril formation in vitro and stabilizes fibrils, and that it is likely to contribute to the persistence of amyloid deposits in vivo. It also says the role of amyloid fibrils in AD pathogenesis, if any, is unknown, while identifying a direct disease-causing role for amyloid in CAA. The claim overstates this qualified account as an established contribution to the pathogenesis of both conditions. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Extensive small ThioS+ fibrillar aggregations are found in bone and bone marrow of 22-month-old mice, with no Aβ amyloid deposits in the same region of 4-month-old mice.

    “Like the finding in AD mice, extensive small ThioS+ fibrillar aggregations were found in the bone and bone marrow of mice at 22 months of age (old) with no Aβ amyloid deposits in the same region of 4-month-old mice (young) (Fig. 2j,k).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SAP/PTX2 concentrations in bone marrow of aged versus young mice and AD mice versus WT littermates were significantly elevated.

    “Furthermore, SAP/PTX2 concentrations in bone marrow of aged (versus young) mice and AD mice (versus WT littermates) were significantly elevated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CPHPC treatment significantly increased BV/TV and Tb.Th, left Tb.N unchanged, and decreased Tb.Sp relative to control.

    “Qualification of the parameters in the trabecular bone showed significantly increased BV/TV and Tb.Th, unchanged Tb.N and decreased Tb.Sp in the CPHPC treatment group relative to the control group (Fig. 7d–g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In both AD mice and naturally aging mice, smaller Aβ deposits are either diffuse in the bone marrow or localized around senescent BMAds, forming unique large, ring-like structures.

    “Intriguingly, in both AD mice and naturally aging mice, smaller Aβ deposits are either diffuse in the bone marrow or localized around senescent BMAds, forming unique large, ring-like structure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SAP/PTX2 levels were markedly elevated in the CM prepared from BMAds isolated from both AD mice and naturally aging mice compared to their control counterparts, and this elevation was mitigated by treating the cells with senolytic drugs.

    “Supporting this notion, SAP/PTX2 levels were markedly elevated in the CM prepared from BMAds isolated from both AD mice and naturally aging mice compared to their control counterparts, and this elevation was mitigated by treating the cells with senolytic drugs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Extensive small ThioS+ fibrillar amyloid deposits are observed in bone and bone marrow of AD mice, while WT mice had no obvious Aβ deposits.

    “While the WT mice had no obvious Aβ deposits in bone and bone marrow, extensive small ThioS+ fibrillar amyloid deposits were observed in AD mice (Fig. 2f,g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    BMAds undergo substantial expansion and display a senescence phenotype in both AD mice and naturally aging mice.

    “BMAds undergo substantial expansion and display a senescence phenotype in both AD mice and naturally aging mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Elevated Aβ peptides and increased amyloid deposits were detected in the bone marrow of both AD mice versus WT mice and naturally aging mice versus young mice.

    “We detected elevated Aβ peptides and increased amyloid deposits in the bone marrow of both AD mice (versus WT mice) and naturally aging mice (versus young mice).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p19+ signal is almost exclusively localized around large, ring-like BMAds in both AD mice and naturally aging mice, with no p19+ signal in WT littermates or young mice.

    “Further RNAscope analysis of bone tissue sections revealed that the p19+ signal was almost exclusively localized around large, ring-like BMAds in both AD mice (Fig. 3i,j) and naturally aging mice (Fig. 3l,m). By contrast, no p19+ signal was detected in WT littermates or young mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Immunostaining of bone tissue sections identified hAPP+ signals in AD mice, but RT-PCR failed to detect the hAPP transgene in flushed bone marrow cells.

    “While immunostaining of bone tissue sections identified hAPP+ signals in AD mice, RT–PCR failed to detect the hAPP transgene in flushed bone marrow cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both transgenic Alzheimer's disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds).

    “Here, we demonstrate that both transgenic Alzheimer’s disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AD mice exhibit notably higher levels of Oil Red O-positive BMAds and a greater percentage of SA-βGal+ BMAds than their WT littermates.

    “When bone tissue sections were co-stained for SA-βGal and with Oil Red O, it was evident that AD mice exhibited notably higher levels of Oil Red O-positive BMAds and a greater percentage of SA-βGal+ BMAds than their WT littermates (Fig. 3a–c), indicating a senescence-like change in BMAds under AD conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CPHPC-treated mice had greatly reduced TRAP+ osteoclasts with much lower surface per bone surface in both trabecular and cortical bone than vehicle-treated mice.

    “By contrast, we observed greatly reduced TRAP+ osteoclasts with much lower surface per bone surface in both trabecular bone (Fig. 7p,q) and cortical bone (Fig. 7p,r) in CPHPC-treated mice than in vehicle-treated mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SAP concentration in whole bone marrow is significantly higher in AD mice and old mice than in age-matched WT littermates and young mice, respectively.

    “Consistently, SAP concentration in whole bone marrow was also significantly higher in AD mice (Extended Data Fig. 5a) and old mice (Extended Data Fig. 5b) than in age-matched WT littermates and young mice, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither increased SAP expression nor H31L21+ amyloid deposits were detected in visceral adipose tissue from either AD mice or naturally aging mice.

    “However, while increased SAP expression and H31L21+ amyloid deposits were observed in BMAds, neither of these two parameters were detected in visceral adipose tissue from either AD mice or naturally aging mice (Extended Data Fig. 7i–l).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adipocytes in visceral adipose tissue showed increased senescent cells in both AD mice compared to WT littermates and aged mice compared to young mice, as indicated by increased p19ARF+ cells and γH2AX+ cells.

    “Similar to BMAds, adipocytes in visceral adipose tissue showed increased senescent cells in both AD mice (compared to WT littermates) and aged mice (compared to young mice), as indicated by increased p19ARF+ cells and γH2AX+ cells (Extended Data Fig. 7a–h).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both transgenic AD mice and naturally aging mice exhibit amyloid deposits in bone marrow.

    “Here, we demonstrate that both transgenic Alzheimer’s disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The humanized APP transgene (hAPP) is expressed in brain tissue but not in bone marrow cells flushed from mice.

    “TaqMan quantitative PCR with reverse transcription (RT–qPCR) analysis of the humanized APP transgene (hAPP) revealed its expression in brain tissue but not in bone marrow cells flushed from mice (Extended Data Fig. 2a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ oligomers are significantly increased in the bone marrow of AD mice and old mice compared to WT littermates and young mice, respectively.

    “Dot blot filter retention assays, a technique that separates insoluble Aβ aggregates from soluble Aβ by retention on a filter membrane, confirmed a significant increase in Aβ oligomers in the bone marrow of AD mice and old mice compared to WT littermates and young mice, respectively (Fig. 2e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Consistent bone results were obtained from the proximal tibia in female mice, the distal femur in male mice, and the proximal tibia in male mice.

    “Consistent results were obtained from the proximal tibia in female mice (Extended Data Fig. 9a–d) as well as the distal femur (Extended Data Fig. 9e–h) and the proximal tibia in male mice (Extended Data Fig. 9i–l).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Acceptors transplanted with BMAds isolated from AD mice had significant bone loss, reduced BV/TV and Tb.Th but unchanged Tb.N and Tb.Sp compared to those transplanted with WT BMAds.

    “µCT analyses revealed that acceptors transplanted with BMAds isolated from AD mice (AD → WT), compared with those transplanted with an equal number of BMAds isolated from WT mice (WT → WT), had significant bone loss (Fig. 5e), reduced BV/TV (Fig. 5f) and Tb.Th (Fig. 5g) but unchanged Tb.N (Fig. 5h) and Tb.Sp (Fig. 5i).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BMAds from both AD mice and old mice show elevated SAP secretion compared to their respective controls.

    “As expected, BMAds from both AD mice (Fig. 6b) and old mice (Fig. 6c) showed elevated SAP secretion compared to their respective controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Combined SAP and Aβ peptide treatment increased osteoclastogenesis of bone marrow monocytes and/or macrophages and inhibited osteoblastogenesis of bone marrow mesenchymal stromal cells.

    “Our in vitro assays demonstrate that combined SAP and Aβ peptide treatment increased osteoclastogenesis of bone marrow monocytes and/or macrophages and inhibited osteoblastogenesis of bone marrow mesenchymal stromal cells, suggesting that SAP-triggered Aβ deposition may regulate the function of both osteoclast and osteoblast lineage cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    While visceral adipose tissue adipocytes exhibit cellular senescence in both AD and aged mice, increased SAP expression or amyloid deposition was not observed in this depot.

    “However, while visceral adipose tissue adipocytes exhibit cellular senescence in both AD and aged mice, we did not observe increased SAP expression or amyloid deposition in this depot.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CPHPC treatment reduces osteoclast number and increases osteoprogenitor cells.

    “Moreover, CPHPC treatment reduces osteoclast number and increases osteoprogenitor cells, indicating the impact of depleting SAP on both osteoclast and osteoblast activities.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Nerve fibers within bone and/or bone marrow may contribute to the elevated human Aβ detected in the bone marrow.

    “As hAPP and PS1 transgenes are predominantly expressed in neurons and astrocytes in the AD mouse line, our findings suggest that nerve fibers within bone and/or bone marrow may contribute to the elevated human Aβ detected in the bone marrow.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: hAPP and PS1 transgenes are predominantly expressed in neurons and astrocytes in the AD mouse line.

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

    Premisecitation

    Bone loss is frequently detected early in the progression of AD, preceding substantial cognitive decline.

    “Patients with osteoporosis often have a higher incidence of AD, and bone loss is frequently detected early in the progression of AD, preceding substantial cognitive decline25–27.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Frame, G., Bretland, K. A. & Dengler-Crish, C. M. Mechanistic complexities of bone loss in Alzheimer’s disease: a review. Connect. Tissue Res. 61, 4–18 (2020). source
    • cites [26] Tan, Z. S. et al. Bone mineral density and the risk of Alzheimer disease. Arch. Neurol. 62, 107–111 (2005). source
    • cites [27] Zhou, R., Zhou, H., Rui, L. & Xu, J. Bone loss and osteoporosis are associated with conversion from mild cognitive impairment to Alzheimer’s disease. Curr. Alzheimer Res. 11, 706–713 (2014). source

  • May combine two claims.

    Interpretationown data

    The in vivo data provide evidence to support the role of SAP in inducing bone amyloidosis, which leads to increased osteoblastic bone formation and decreased osteoclastic bone resorption.

    “Together, the in vivo data provide evidence to support the role of SAP in inducing bone amyloidosis, which leads to increased osteoblastic bone formation and decreased osteoclastic bone resorption.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    While p16Ink4a and p19Arf are in the same locus and share overlapping coding regions, they are independently activated in BMAds via distinct mechanisms during aging or in AD conditions.

    “The data suggest that, while p16Ink4a and p19Arf are in the same locus and share overlapping coding regions, they are independently activated in BMAds via distinct mechanisms during aging or in AD conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    71.06% ± 4.28% of cells were BODIPY+ and 74.92% ± 3.63% were perilipin+, validating that the majority of isolated bone marrow cells were live, mature adipocytes.

    “Our results showed that 71.06% ± 4.28% of cells were BODIPY+ (Extended Data Fig. 3b,c) and 74.92% ± 3.63% were perilipin+ (Extended Data Fig. 3d,e), validating that the majority of the isolated bone marrow cells in our approach were live, mature adipocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Despite the distinct sources of bone marrow Aβ in AD mice and naturally aging mice, evidence from this study strongly supports that senescent BMAds, under both AD and aging conditions, secrete SAP/PTX2, which stabilizes Aβ peptides and promotes amyloid deposition in the bone marrow.

    “Despite the distinct sources of bone marrow Aβ in AD mice and naturally aging mice, evidence from this study strongly supports that senescent BMAds, under both AD and aging conditions, secrete SAP/PTX2, which stabilizes Aβ peptides and promotes amyloid deposition in the bone marrow.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Senescent BMAds in AD mice and aged mice secrete significantly higher amounts of SAP/PTX2, thereby promoting the formation of insoluble Aβ aggregates.

    “Indeed, our in vitro and in vivo assays reveal that senescent BMAds in AD mice and aged mice secrete significantly higher amounts of SAP/PTX2, thereby promoting the formation of insoluble Aβ aggregates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Senescent BMAds drive age-related skeletal amyloidosis and bone deficits via SAP/PTX2.

    “Thus, senescent BMAds drive age-related skeletal amyloidosis and bone deficits via SAP/PTX2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Although senescent adipocytes accumulate in both bone marrow and peripheral tissue under AD and aging conditions, only BMAds secrete SAP/PTX2 to promote amyloid deposition specifically in bone marrow.

    “Therefore, although senescent adipocytes accumulate in both bone marrow and peripheral tissue under AD and aging conditions, only BMAds secrete SAP/PTX2 to promote amyloid deposition specifically in bone marrow.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Aβ aggregate formation induced by SAP promotes osteoclastogenesis but inhibits osteoblastogenesis.

    “The results suggest that Aβ aggregate formation induced by SAP promotes osteoclastogenesis but inhibits osteoblastogenesis.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Approximately 94.19% ± 1.66% and 79.48% ± 2.79% of BMAds were viable immediately after isolation and following a 3-d culture, respectively.

    “Approximately 94.19% ± 1.66% and 79.48% ± 2.79% of the cells were viable immediately after isolation and following a 3-d culture, respectively, as determined by Trypan blue dye exclusion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Senescent BMAds acquire a secretory phenotype, leading to the secretion of elevated levels of SAP/PTX2, which in turn stabilizes amyloid fibrils and promotes amyloidogenesis around BMAds.

    “These senescent BMAds acquire a secretory phenotype, leading to the secretion of elevated levels of SAP/PTX2, which in turn stabilizes amyloid fibrils and promotes amyloidogenesis around BMAds.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Low bone mineral density can predict risk of AD years before dementia diagnosis.

    “Notably, low bone mineral density can predict risk of AD years before dementia diagnosis26,28,29.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] Tan, Z. S. et al. Bone mineral density and the risk of Alzheimer disease. Arch. Neurol. 62, 107–111 (2005). source
    • cites [28] Amouzougan, A. et al. High prevalence of dementia in women with osteoporosis. Joint Bone Spine 84, 611–614 (2017). source
    • cites [29] Zhou, R., Deng, J., Zhang, M., Zhou, H. D. & Wang, Y. J. Association between bone mineral density and the risk of Alzheimer’s disease. J. Alzheimers Dis. 24, 101–108 (2011). source

  • May combine two claims.

    Interpretationown data

    The presence of amyloid fibrils triggers osteoclast differentiation and impedes osteoblastogenesis, ultimately resulting in bone loss.

    “The presence of amyloid fibrils triggers osteoclast differentiation and impedes osteoblastogenesis, ultimately resulting in bone loss (Supplementary Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Senescent BMAd-secreted SAP/PTX2 is a major contributor to bone marrow amyloidosis and subsequent bone impairment.

    “Our study reveals that senescent BMAd-secreted SAP/PTX2 is a major contributor to bone marrow amyloidosis and subsequent bone impairment.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    SAP is universally present in all human amyloid deposits.

    “It has been well established that SAP is universally present in all human amyloid deposits68,84.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] Pepys, M. B., Dyck, R. F., de Beer, F. C., Skinner, M. & Cohen, A. S. Binding of serum amyloid P-component (SAP) by amyloid fibrils. Clin. Exp. Immunol. 38, 284–293 (1979).
    • cites [84] Pepys, M. B. et al. Amyloid P component. A critical review. Amyloid 4, 274–295 (1997). source

  • May combine two claims.

    Interpretationown data

    Depleting SAP impacts both osteoclast and osteoblast activities.

    “Moreover, CPHPC treatment reduces osteoclast number and increases osteoprogenitor cells, indicating the impact of depleting SAP on both osteoclast and osteoblast activities.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Representative images of bones or cells were chosen from a minimum of three independent experiments with consistent results unless specified otherwise in the figure legend.

    “Representative images of bones or cells were chosen from a minimum of three independent experiments with consistent results unless specified otherwise in the figure legend.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    CPHPC was developed based on the human SAP sequence, and its SAP depletion effect has primarily been tested in humans.

    “It is important to note that CPHPC was developed based on the human SAP sequence, and its SAP depletion effect has primarily been tested in humans.”
    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 conductreasoning

    To quantify fluorescence intensity around BMAds, mean fluorescence intensity was quantified at the same bone regions, with five fields of view per sample and five samples per group, a standardized method that avoided bias from arbitrary field selection and ensured reliable quantification.

    “To quantify fluorescence intensity around BMAds in immunofluorescence staining and RNAscope, the mean fluorescence intensity was quantified to ensure accurate and consistent data representation. Analysis was performed at the same bone regions (distal femur), maintaining consistency across all samples. For each sample, five fields of view were selected and analyzed, and a total of five samples were”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Sample size was not predetermined using statistical methods.

    “Sample size was not predetermined using statistical methods”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Data shown are from one representative experiment (with n ≥ 3 per group) of at least two independent experiments.

    “Data shown are from one representative experiment (with n ≥ 3 per group) of at least two independent experiments.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Data collection and analysis were performed unblinded to the age of the mice.

    “Data collection and analysis were performed unblinded to the age of the mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Although adipocytes in other adipose tissues undergo senescence under AD and aging conditions, only BMAds secrete SAP/PTX2, driving amyloid deposition specifically in the bone marrow.

    “These findings suggest that, although adipocytes in other adipose tissues undergo senescence under AD and aging conditions, only BMAds secrete SAP/PTX2, driving amyloid deposition specifically in the bone marrow.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Cell viability and purity were assessed after adipocyte isolation using Trypan blue, LIVE/DEAD Cell Imaging Kit, BODIPY with DAPI staining, and perilipin immunostaining.

    “Cell viability and purity were assessed after adipocyte isolation. Cell viability was assessed using Trypan blue and the LIVE/DEAD Cell Imaging Kit (488/570) (Thermo Fisher Scientific, R37601). To assess purity and maturity, BODIPY with DAPI staining was performed on live cells, and perilipin immunostaining was conducted on fixed cells, both of which are standard markers for mature adipocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Senescent BMAd-secreted SAP/PTX2 efficiently triggers the formation of insoluble amyloid fibrils from soluble Aβ peptide, providing evidence for the role of SAP in stabilizing amyloid fibrils in peripheral tissue.

    “Our results from filter retention assays and 3D amyloid deposition assays demonstrate that senescent BMAd-secreted SAP/PTX2 efficiently triggers the formation of insoluble amyloid fibrils from soluble Aβ peptide, providing evidence for the role of SAP in stabilizing amyloid fibrils in peripheral tissue.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    A minimum of three samples were included per experimental group and condition.

    “a minimum of three samples were included per experimental group and condition”
    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 animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee under protocols MO21M37 and MO24M35, in full compliance with institutional guidelines.

    “All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee under protocols MO21M37 and MO24M35, in full compliance with institutional guidelines.”
    Quote in the paperNot a substantial claim
66 of 66

  • The paper relies on this without support.

    There has been no investigation into whether amyloidosis occurs in bone or bone marrow with age or under conditions of AD.

    “While amyloid depositions have been reported in several organs of aged patients such as knee joints, intervertebral disks and the ligamentum flavum32–34, there has been no investigation into whether amyloidosis also occurs in bone or bone marrow with age or under conditions of AD and how it may contribute to any pathologic consequences in the skeleton.”

  • The paper relies on this without support.

    hAPP and PS1 transgenes are predominantly expressed in neurons and astrocytes in the AD mouse line.

    “As hAPP and PS1 transgenes are predominantly expressed in neurons and astrocytes in the AD mouse line, our findings suggest that nerve fibers within bone and/or bone marrow may contribute to the elevated human Aβ detected in the bone marrow.”

  • The paper relies on this without support.

    All data exhibited normal distribution.

    “All data exhibited normal distribution”

  • The paper relies on this without support.

    All data had comparable variation between groups.

    “had comparable variation between groups”
4 of 4

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.

  • Aged mice in Fig. 2 are reported as both 22 and 24 months old

    Major

    The Results describe the old mice in Fig. 2c,d as 22 months old, while the figure legend identifies the same comparison as using 24-month-old mice.

  • Filter retention assay duration differs between legend and Methods

    Major

    The Fig. 6 legend specifies three days of Aβ exposure before the filter retention assay, whereas the Methods specify two weeks before the cultured cells were processed for that assay.

  • Fig. 6 RNAscope specimens are called both femoral and tibial

    Minor

    The Results identify the bones examined for the p21/SAP signals in Fig. 6d,e as femoral, but the figure legend identifies them as tibial.

  • Fig. 6 legend assigns filter retention results to the staining panels

    Minor

    The legend places filter retention results in panels j-m, but the Results identify panel i as the filter retention assay; the legend itself describes j-m as Congo red and ThioS images and quantifications.

  • Conclusion reverses the reported effects of amyloid on bone cells

    Minor

    The Results say SAP-induced bone amyloidosis leads to increased osteoblastic formation and decreased osteoclastic resorption. Elsewhere, the paper says amyloid promotes osteoclast differentiation and impedes osteoblastogenesis-the opposite directions.

5 of 5

Cites

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1 of the 116 references couldn’t be matched to a known paper.

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Related

Authors
Kumar, S., Song, K., Wang, J., Baghel, M. S., Zeng, Y., Shen, K., Zheng, J., Crane, J., Demehri, S., Gao, P., Jain, A., Skolasky, R. L., Wong, P., Cao, X., & Wan, M.
Affiliations
Johns Hopkins University (US)
Corresponding author
Wan, Mei
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2025-07-29
Volume
5
Issue
9
Pages
1771-1789
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-025-00924-z
PMC
PMC12443615
OpenAlex
W4412785836
Cited by
16
References
116
Citations by year
2026: 14 · 2025: 2
FWCI
4.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Aging (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG068226, R01AG072090, P01AG066603)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
Keywords
serum amyloid P component, bone marrow adipocytes, cellular senescence, amyloid-beta, osteoclastogenesis, osteoblastogenesis, bone loss, senolytics, aging, Alzheimer's disease, bone marrow

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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.

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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-30.

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