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Osteocyte-derived sclerostin impairs cognitive function during ageing and Alzheimer’s disease progression

Nature Metabolism volume 6, pages 531–549 (2024)Cite this article

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Abstract

Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer’s disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt–β-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt–β-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood–brain barrier of old mice, where it can dysregulate Wnt–β-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid β (Aβ) production through β-catenin–β-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αβ production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone–brain crosstalk, which could serve as a target for developing therapeutic interventions against AD.

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Fig. 1: Osteocyte-derived sclerostin mediates canonical Wnt signalling deregulation in the brain during ageing.
Fig. 2: Boosting osteocyte-derived sclerostin levels impairs synaptic plasticity in the brain and cognitive function in aged mice.
Fig. 3: Decreasing osteocyte-derived sclerostin levels alleviate cognitive impairment and synaptic deficits in aged mice.
Fig. 4: Sclerostin accelerates Αβ production via the β-catenin–BACE1 pathway.
Fig. 5: Increased osteocyte-derived sclerostin secretion accelerates Αβ production and cognitive decline in AD model mice.
Fig. 6: Increased serum sclerostin is correlated with cognitive impairment in both ageing and individuals with AD.
Fig. 7: Scl-Ab alleviates memory impairment in AD mice with high serum sclerostin levels.

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References

  1. Piehl, N. et al. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell 185, 5028–5039 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54, 412–436 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sahay, A. et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Ray, S. et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat. Med. 13, 1359–1362 (2007).

    CAS  PubMed  Google Scholar 

  6. Yousef, H. et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat. Med. 25, 988–1000 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Perrin, R. J. et al. Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer’s disease. PLoS ONE 6, e16032 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ohrfelt, A. et al. Increased cerebrospinal fluid levels of ubiquitin carboxyl-terminal hydrolase L1 in patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Dis. Extra 6, 283–294 (2016).

    PubMed  PubMed Central  Google Scholar 

  10. McAlpine, C. S. et al. Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease. Nature 595, 701–706 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lourenco, M. V. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat. Med. 25, 165–175 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. During, M. J. et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat. Med. 9, 1173–1179 (2003).

    CAS  PubMed  Google Scholar 

  14. Han, Y., You, X., Xing, W., Zhang, Z. & Zou, W. Paracrine and endocrine actions of bone—the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res. 6, 16 (2018).

    PubMed  PubMed Central  Google Scholar 

  15. White, K. E. et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).

    CAS  Google Scholar 

  16. Oury, F. et al. Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155, 228–241 (2013).

    CAS  PubMed  Google Scholar 

  17. Ferron, M., Hinoi, E., Karsenty, G. & Ducy, P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc. Natl Acad. Sci. USA 105, 5266–5270 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mosialou, I. et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 543, 385–390 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887 (2005).

    CAS  PubMed  Google Scholar 

  20. Poole, K. E. et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 19, 1842–1844 (2005).

    CAS  PubMed  Google Scholar 

  21. Pelletier, S., Dubourg, L., Carlier, M.-C., Hadj-Aissa, A. & Fouque, D. The relation between renal function and serum sclerostin in adult patients with CKD. Clin. J. Am. Soc. Nephrol. 8, 819–823 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Bouaziz, W. et al. Loss of sclerostin promotes osteoarthritis in mice via β-catenin-dependent and -independent Wnt pathways. Arthritis Res. Ther. 17, 24 (2015).

    PubMed  PubMed Central  Google Scholar 

  23. Papadopoulou, A. et al. Human placental LRP5 and sclerostin are increased in gestational diabetes mellitus pregnancies. J. Clin. Endocrinol. Metab. 108, 2666–2675 (2023).

    PubMed  PubMed Central  Google Scholar 

  24. Kim, S. P. et al. Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc. Natl Acad. Sci. USA 114, E11238–E11247 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mirza, F. S., Padhi, I. D., Raisz, L. G. & Lorenzo, J. A. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J. Clin. Endocrinol. Metab. 95, 1991–1997 (2010).

    PubMed  PubMed Central  Google Scholar 

  26. Ardawi, M.-S. M. et al. High serum sclerostin predicts the occurrence of osteoporotic fractures in postmenopausal women: the Center of Excellence for Osteoporosis Research Study. J. Bone Miner. Res. 27, 2592–2602 (2012).

    CAS  PubMed  Google Scholar 

  27. Liu, C.-C. et al. Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer’s disease. Neuron 84, 63–77 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Heppt, J. et al. β-Catenin signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons. EMBO J. 39, e104472 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cerpa, W. et al. Wnt-5a occludes Aβ oligomer-induced depression of glutamatergic transmission in hippocampal neurons. Mol. Neurodegener. 5, 3 (2010).

    PubMed  PubMed Central  Google Scholar 

  30. Yu, F., Zhang, Y. & Chuang, D.-M. Lithium reduces BACE1 overexpression, β amyloid accumulation, and spatial learning deficits in mice with traumatic brain injury. J. Neurotrauma 29, 2342–2351 (2012).

    PubMed  PubMed Central  Google Scholar 

  31. Fortress, A. M., Schram, S. L., Tuscher, J. J. & Frick, K. M. Canonical Wnt signaling is necessary for object recognition memory consolidation. J. Neurosci. 33, 12619–12626 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Palomer, E., Buechler, J. & Salinas, P. C. Wnt signaling deregulation in the aging and Alzheimer’s brain. Front. Cell. Neurosci. 13, 227 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lee, S. J., Song, S. Y. & Rhee, Y. Skeletal changes during lactation and after weaning in osteocyte-specific sclerostin overexpressed mice. J. Bone Miner. Metab. 38, 172–178 (2020).

    CAS  PubMed  Google Scholar 

  34. Yang, Y.-S. et al. Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis. Nat. Commun. 10, 2958 (2019).

    PubMed  PubMed Central  Google Scholar 

  35. Cai, H. et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat. Neurosci. 4, 233–234 (2001).

    CAS  PubMed  Google Scholar 

  36. Luckhaus, C. et al. Blood biomarkers of osteoporosis in mild cognitive impairment and Alzheimer’s disease. J. Neural Transm. 116, 905–911 (2009).

    CAS  PubMed  Google Scholar 

  37. Chang, K.-H. et al. Increased risk of dementia in patients with osteoporosis: a population-based retrospective cohort analysis. Age 36, 967–975 (2014).

    PubMed  Google Scholar 

  38. Bliuc, D. et al. Cognitive decline is associated with an accelerated rate of bone loss and increased fracture risk in women: a prospective study from the Canadian Multicentre Osteoporosis Study. J. Bone Miner. Res. 36, 2106–2115 (2021).

  39. Koseoglu, E. et al. Nasu Hakola disease: a rare cause of dementia and cystic bone lesions, report of a new Turkish family. Noro Psikiyatr. Ars. 55, 98–102 (2018).

    Google Scholar 

  40. Bianchin, M. M., Martin, K. C., de Souza, A. C., de Oliveira, M. A. & Rieder, C. R. d. M. Nasu–Hakola disease and primary microglial dysfunction. Nat. Rev. Neurol. 6, 523 (2010).

    PubMed  Google Scholar 

  41. Xiong, J. et al. FSH blockade improves cognition in mice with Alzheimer’s disease. Nature 603, 470–476 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hay, E., Bouaziz, W., Funck-Brentano, T. & Cohen-Solal, M. Sclerostin and bone aging: a mini-review. Gerontology 62, 618–623 (2016).

    CAS  PubMed  Google Scholar 

  43. Lee, J.-W., Lee, I.-H., Iimura, T. & Kong, S. W. Two macrophages, osteoclasts and microglia: from development to pleiotropy. Bone Res. 9, 11 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Modder, U. I. et al. Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J. Bone Miner. Res. 26, 373–379 (2011).

    CAS  PubMed  Google Scholar 

  45. Register, T. C. et al. Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the African American-Diabetes Heart Study. J. Clin. Endocrinol. Metab. 99, 315–321 (2014).

    CAS  PubMed  Google Scholar 

  46. Amrein, K. et al. Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J. Clin. Endocrinol. Metab. 97, 148–154 (2012).

    CAS  PubMed  Google Scholar 

  47. Sheng, Z. et al. Serum sclerostin levels were positively correlated with fat mass and bone mineral density in central south Chinese postmenopausal women. Clin. Endocrinol. 76, 797–801 (2012).

    CAS  Google Scholar 

  48. Rhee, Y., Kim, W. J., Han, K. J., Lim, S. K. & Kim, S. H. Effect of liver dysfunction on circulating sclerostin. J. Bone Miner. Metab. 32, 545–549 (2014).

    CAS  PubMed  Google Scholar 

  49. Pietrzyk, B., Smertka, M. & Chudek, J. Sclerostin: intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders. Adv. Clin. Exp. Med. 26, 1283–1291 (2017).

    PubMed  Google Scholar 

  50. Reppe, S. et al. Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. J. Bone Miner. Res. 30, 249–256 (2015).

    CAS  PubMed  Google Scholar 

  51. Clarke, B. L. & Drake, M. T. Clinical utility of serum sclerostin measurements. Bonekey Rep. 2, 361 (2013).

    PubMed  PubMed Central  Google Scholar 

  52. Folke, J., Pakkenberg, B. & Brudek, T. Impaired Wnt signaling in the prefrontal cortex of Alzheimer’s disease. Mol. Neurobiol. 56, 873–891 (2019).

    CAS  PubMed  Google Scholar 

  53. Pardridge, W. M. Blood–brain barrier delivery. Drug Discov. Today 12, 54–61 (2007).

    CAS  PubMed  Google Scholar 

  54. Ye, X. et al. Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell 139, 285–298 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Benchenane, K. et al. Tissue-type plasminogen activator crosses the intact blood–brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation 111, 2241–2249 (2005).

    CAS  PubMed  Google Scholar 

  56. Lajoie, J. M. & Shusta, E. V. Targeting receptor-mediated transport for delivery of biologics across the blood–brain barrier. Annu. Rev. Pharmacol. Toxicol. 55, 613–631 (2015).

    CAS  PubMed  Google Scholar 

  57. Jiang, Y.-L. et al. The protective effects of osteocyte-derived extracellular vesicles against Alzheimer’s disease diminished with aging. Adv. Sci. 9, e2105316 (2022).

    Google Scholar 

  58. Kiecker, C. The origins of the circumventricular organs. J. Anat. 232, 540–553 (2018).

    PubMed  Google Scholar 

  59. Abe, T. et al. Lipoprotein receptor-related protein-6 protects the brain from ischemic injury. Stroke 44, 2284–2291 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Bell, R. D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Wojtunik-Kulesza, K., Rudkowska, M. & Orzel-Sajdlowska, A. Aducanumab—hope or disappointment for Alzheimer’s disease. Int. J. Mol. Sci. 24, 4367 (2023).

  62. Parr, C., Mirzaei, N., Christian, M. & Sastre, M. Activation of the Wnt/β-catenin pathway represses the transcription of the β-amyloid precursor protein cleaving enzyme (BACE1) via binding of T-cell factor-4 to BACE1 promoter. FASEB J. 29, 623–635 (2015).

    CAS  PubMed  Google Scholar 

  63. Chen, S., Underwood, B. R., Jones, P. B., Lewis, J. R. & Cardinal, R. N. Association between lithium use and the incidence of dementia and its subtypes: a retrospective cohort study. PLoS Med. 19, e1003941 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhao, J. et al. GRK5 influences the phosphorylation of tau via GSK3β and contributes to Alzheimer’s disease. J. Cell. Physiol. 234, 10411–10420 (2019).

    CAS  PubMed  Google Scholar 

  65. Chacon, M. A., Varela-Nallar, L. & Inestrosa, N. C. Frizzled-1 is involved in the neuroprotective effect of Wnt3a against Aβ oligomers. J. Cell. Physiol. 217, 215–227 (2008).

    CAS  PubMed  Google Scholar 

  66. Hadi, F., Akrami, H., Shahpasand, K. & Fattahi, M. R. Wnt signalling pathway and tau phosphorylation: a comprehensive study on known connections. Cell Biochem. Funct. 38, 686–694 (2020).

    CAS  PubMed  Google Scholar 

  67. Suryawanshi, A. et al. Canonical Wnt signaling in dendritic cells regulates TH1/TH17 responses and suppresses autoimmune neuroinflammation. J. Immunol. 194, 3295–3304 (2015).

    CAS  PubMed  Google Scholar 

  68. Pulous, F. E. et al. Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis. Nat. Neurosci. 25, 567–576 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Rustenhoven, J. & Kipnis, J. Brain borders at the central stage of neuroimmunology. Nature 612, 417–429 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lyons, J. S. et al. Microtubules tune mechanotransduction through NOX2 and TRPV4 to decrease sclerostin abundance in osteocytes. Sci. Signal. 10, eaan5748 (2017).

  71. Stillman, C. M., Esteban-Cornejo, I., Brown, B., Bender, C. M. & Erickson, K. I. Effects of exercise on brain and cognition across age groups and health states. Trends Neurosci. 43, 533–543 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Chang, J. C. et al. SOST/sclerostin improves posttraumatic osteoarthritis and inhibits MMP2/3 expression after injury. J. Bone Miner. Res. 33, 1105–1113 (2018).

    PubMed  Google Scholar 

  73. Zhang, G. et al. A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy. Nat. Med. 18, 307–314 (2012).

    PubMed  Google Scholar 

  74. Bevins, R. A. & Besheer, J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nat. Protoc. 1, 1306–1311 (2006).

    PubMed  Google Scholar 

  75. Vorhees, C. V. & Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848–858 (2006).

    PubMed  PubMed Central  Google Scholar 

  76. Hwang, L. et al. Dexmedetomidine ameliorates memory impairment in sleep-deprived mice. Anim. Cells Syst. 23, 371–379 (2019).

    CAS  Google Scholar 

  77. David, D. J. et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479–493 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by research grants from the National Key Research and Development Project (2021YFA1201404), the Major Project of NSFC (81991514), the National Key Research and Development Program of China (2020YFC2004900), the National Natural Science Foundation of China (82272530, 82000069, 82002370, 81972124), the Youth Thousand Talents Program of China (13004001), the Jiangsu Province Medical Innovation Center of Orthopedic Surgery (CXZX202214), the Jiangsu Provincial Key Medical Center Foundation, the Jiangsu Provincial Medical Outstanding Talent Foundation, the Jiangsu Provincial Medical Youth Talent Foundation, the Jiangsu Provincial Key Medical Talent Foundation, the Fundamental Research Funds for the Central Universities (14380493, 14380494), the Natural Science Foundation of Jiangsu Province of China (BK20200314, BK20200117), the Research Team Start-up Funds of Nanjing University (14912203), the Program of Innovation and Entrepreneurship of Jiangsu Province, the China Postdoctoral Science Foundation (2019M661806) and the Jiangsu postdoctoral research support project (2021K059A). This work is to my father, who suffers from dementia, from your son Qing.

Author information

Author notes

  1. These authors contributed equally: Tianshu Shi, Siyu Shen, Yong Shi.

Authors and Affiliations

  1. Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China

    Tianshu Shi, Siyu Shen, Yong Shi, Qianjin Wang, Jiaquan Lin, Lei Zhang, Yangyufan Wang, Wang Gong, Xiaoyan Shao, Wenjin Yan, Xiang Chen, Yuze Ma, Liming Zheng, Jianghui Qin, Ke Lu, Na Liu, Qing Jiang & Baosheng Guo

  2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China

    Tianshu Shi, Siyu Shen, Yong Shi, Qianjin Wang, Jiaquan Lin, Lei Zhang, Yangyufan Wang, Wang Gong, Xiaoyan Shao, Wenjin Yan, Xiang Chen, Yuze Ma, Liming Zheng, Jianghui Qin, Ke Lu, Na Liu, Qing Jiang & Baosheng Guo

  3. Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, PR China

    Tianshu Shi, Siyu Shen, Yong Shi, Qianjin Wang, Jiaquan Lin, Lei Zhang, Yangyufan Wang, Wang Gong, Xiaoyan Shao, Wenjin Yan, Xiang Chen, Yuze Ma, Liming Zheng, Jianghui Qin, Ke Lu, Na Liu, Qing Jiang & Baosheng Guo

  4. Department of Neurology, the Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, PR China

    Guanqun Zhang

  5. Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, PR China

    Jiaquan Lin, Xiaoyan Shao, Xiang Chen, Na Liu & Baosheng Guo

  6. Department of Neurology, Nanjing Drum Tower Hospital of the Affiliated Hospital of Nanjing University Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China

    Jiang Chen, Feng Bai & Yun Xu

  7. Key Laboratory of Model Animal for Disease Study, Ministry of Education, Model Animal Research Center, Medical School, Nanjing University, Nanjing, China

    Guiquan Chen & Yun Stone Shi

  8. Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Ke Lu

  9. Institute for Brain Sciences, Nanjing University, Nanjing, China

    Yun Stone Shi

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  1. Tianshu Shi
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  2. Siyu Shen
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  3. Yong Shi
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Contributions

B.G., Q.J. and Y.S.S. conceived and designed the work; T.S. and S.S. obtained data; T.S., S.S., Y.S. and W.G. performed behavioural studies; Q.W., G.Z., Y.S., F.B., W.Y., Y.W. and Y.X. collected and analysed patient data; J.C. performed the LTP test; J.L., X.S., L. Zheng, N.L. and Y.M. performed in vitro studies; X.C., G.C., J.Q., K.L. and L. Zhang assisted with histological analysis; T.S. wrote the paper; B.G., Q.J. and Y.S.S. revised the paper.

Corresponding authors

Correspondence to Yun Stone Shi, Qing Jiang or Baosheng Guo.

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The authors declare no competing interests.

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Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Osteocyte-derived sclerostin mediates the canonical Wnt signaling deregulation in aged brain.

A-C. Assessment of the cognitive function of 22- and 12-month-old male mice by the MWM test. Representative a heat map summary of the test day (A). The number of crossings (B) and the percentage of time spent in platform quadrant (C) in 90 s in the probe trial (n = 8 for each group). D-E. Western blot detection (D) and the grey value analysis (E) of β-catenin and sclerostin in the cortices and hippocampi of 12- and 22-month-old female mice (n = 3 biological samples for each group). F. Correlation analysis of sclerostin levels in the CSF in different aged men (Left) and women (Right). G. Q-PCR analysis of the mRNA expression of Lrp4, Lrp5 and Lrp6 in the cortices and hippocampi of aged male mice (n = 9 for each group). H. Western blot analysis of Lrp6 protein expression in the cortices and hippocampi of aged male mice (n = 2 biological samples for each group). I. Analysis of serum sclerostin levels in male WT and KO mice by ELISA (n = 4 for each group). J. Western blot analysis of sclerostin levels in the cortices and hippocampi of male WT and KO mice (n = 2 biological samples for each group). K. Immunofluorescent staining of sclerostin in the hippocampi of Sost-KO mice after tail vein injection of WT mouse serum or r-sclerostin protein. L. Western blots and grey value analysis for the active β-catenin levels treated with the CSF from the young and old group with and without sclerostin neutralizing antibody (n = 3 biological samples for each group). M. The constructive graph of osteocyte-special Sost knockout mice. N. The immunohistochemical staining for sclerostin in Sost-cKO mice. O. Western blot detection and the grey value analysis of β-catenin level in the cortices and hippocampi of female Sost-cKO mice (n = 3 biological samples for each group). Notes: Data are represented as mean ± SEM. One-way ANOVA followed by Tukey’s multiple comparisons test (G, L); two-tailed Spearman’s correlation analysis (F); and two-tailed unpaired t-test (B, C, E, I, O).

Source data

Extended Data Fig. 2 Increasing sclerostin levels impairs synaptic plasticity and cognitive function in aged mice.

A. Analysis of serum sclerostin levels in 12-month-old aged male SOST-WT and TG mice by ELISA (n = 8 WT mice, n = 8 TG mice). B-D. Bone histomorphometric analysis of bone formation in distal femur as measured by Masson’s trichrome staining. The arrows indicate osteoblasts accumulating around osteoids (B). Histomorphometric analysis of bone formation parameters, including Ob.N/BS (C) and Ob.S/BS (D) (n = 10 bone slides from WT mice, n = 14 bone slides from TG mice). E-G. Assessment of athletic ability, anxiety and depression. Representative heat maps of the mice are shown (E). Athletic ability, including the average speed and total distance traveled, is shown (F). Anxiety and depression behaviors, including the time spent in the central area and the distance traveled in the central area, are shown (G) (n = 18 WT mice, n = 18 TG mice). H-I. Analysis of synaptic plasticity by measuring LTP in 3-month-old male SOST-TG and WT mice (n = 9 brain slices from WT mice, n = 8 brain slices from TG mice). fEPSPs (H) and average LTP (I) are shown for SOST-TG and WT mice. J-M. Western blot (J) and grey analysis (K-M) of the synaptic plasticity and integrity markers (n = 3 biological samples for each group). N-O. Golgi staining of apical and basal dendritic spines in the cortex and hippocampus (n = 20 brain slices from aged mice for each group). Notes: Data are represented as mean ± SEM. Two-tailed unpaired t-test (A, C, D, F, G, I, K, L, M, N, O); Repeated-measures two-way ANOVA test (H).

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Extended Data Fig. 3 Boosting osteocyte-derived sclerostin levels impairs synaptic plasticity and cognitive function in aged mice.

A. Design of the bone-targeting rAAV9-DSS-Nter-Sost construct. B. Representative images of immunohistochemical staining of sclerostin in bone tissue. C. Analysis of serum sclerostin levels in 12-month-old male mice treated with rAAV9-DSS-Nter-Sost for two months and untreated aged WT mice by ELISA (n = 8 rAAV9-DSS-Nter-Ctrl mice, n = 8 rAAV9-DSS-Nter-Sost mice). D-F. Bone histomorphometric analysis of the distal femur. Representative images of Masson’s trichrome staining (D). Histomorphometric analysis of bone formation parameters, including Ob.N/BS (E) and Ob.S/BS (F) (n = 12 bone slides of rAAV9-DSS-Nter-Ctrl mice, n = 6 bone slides of rAAV9-DSS-Nter-Sost mice). G-H. Assessment of athletic ability, anxiety and depression (n = 15 rAAV9-DSS-Nter-Ctrl mice, n = 15 rAAV9-DSS-Nter-Sost mice). Representative heat maps of the mice are shown (G). Athletic ability, anxiety and depression assessment, including the average speed, the time spent in the central area, and the distance traveled in the central area, are shown (H). I-J. Western blot and the grey value analysis for the β-catenin and the synaptic markers in rAAV9-DSS-Nter-Ctrl and -Sost mice. (n = 3 biological samples for each group). K-L. Golgi staining of apical and basal dendritic spines in the cortex and hippocampus (n = 20 brain slices from aged mice for each group). Notes: MWM: Morris water maze, NOR: novel object recognition, IAT: inhibitory avoidance task. Notes: Data are represented as mean ± SEM. Two-tailed unpaired t-test (C, E, F, H, J, K, L).

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Extended Data Fig. 4 Boosting osteocyte-derived sclerostin levels impairs synaptic plasticity and cognitive function in aged mice.

A. The constructive graph of osteocyte-special SOST knock-in (KI) mice. B. Q-PCR analysis of Sost mRNA expression levels in bone and other tissues, including lung, spleen, muscle, heart, kidney, liver, and brain tissues, from 6-month-old male KI and WT mice (n = 6 SOST-KI mice, n = 6 WT mice). C. The sclerostin levels in bone tissues from the SOST knock-in and WT mice were detected by IHC staining. D. Analysis of serum sclerostin levels in 6-month-old male KI and WT mice (n = 10 SOST-KI male mice, n = 6 WT male mice). E-F. Immunohistochemical staining (E) and the number of c-Fos-positive cells (F) in the dentate gyrus of the hippocampus in 6-month-old male KI and WT mice (n = 20 brain slices from WT-male mice, n = 15 brain slices from KI male mice). G. Western blot and grey value analysis for the synaptic markers in 6-month-old male KI and WT mice (n = 3 biological samples for each group). H. Analysis of serum sclerostin levels in 6-month-old female KI and WT mice (n = 4 SOST-KI female mice, n = 4 WT female mice). I-J. Immunohistochemical staining (I) and the number of c-Fos-positive cells (J) in the dentate gyrus of the hippocampus in 6-month-old female KI and WT mice (n = 20 brain slices from WT/KI female mice). K. Western blot and grey value analysis for the synaptic markers in 6-month-old KI and WT female mice (n = 3 biological samples for each group). Notes: Data are represented as mean ± SEM. Two-tailed unpaired t-test (B, D, F, G, H, J, K).

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Extended Data Fig. 5 Decreasing osteocyte-derived sclerostin levels alleviates cognitive impairment and synaptic deficits in aged mice.

A-E. Assessment of athletic ability, anxiety, and depression. Heat map summary for the open field test (A). Athletic ability, including total distance (B) and average speeds (C), is shown. Anxiety and depression behaviors, including the distance traveled in the central area (D) and the time spent in the central area (E). (n = 10 Sost-WT male mice, n = 10 Sost-cKO male mice). Notes: Data are represented as mean ± SEM. Two-tailed unpaired t-test (B, C, D, E).

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Extended Data Fig. 6 Decreasing osteocyte-derived sclerostin levels alleviates cognitive impairment and synaptic deficits in aged mice.

A. Design of the bone-targeting rAAV9-DSS-Nter-shSost construct. B. Q-PCR analysis of the expression of Sost mRNA in 293 T cells after transfection with shSost. The sites of shSost1, shSost2 and shSost3 were 65–83, 124–142 and 237–255, respectively (n = 3 biological samples). C. Representative images of immunohistochemical staining for sclerostin in osteocytes from 15-month-old male mice after rAAV9.DSS-Nter-shSost or -Ctrl injection. D. Analysis of serum sclerostin levels by ELISA (n = 7 rAAV9.DSS-Nter-Ctrl mice, n = 12 rAAV9.DSS-Nter-shSost mice). E-F. Histomorphometric analysis of bone formation parameters, including Ob. N/BS and Ob.S/BS.(n = 15 slides from n = 5 Ctrl mice, n = 10 slides from n = 5 shSost mice). G. Performance in the step-down IAT (n = 16 for rAAV9.DSS-Nter-Ctrl mice, n = 15 for rAAV9. DSS-Nter-shSost mice). H-K. Assessment of athletic ability, anxiety and depression. Athletic ability, including average speed (H) and total distance traveled (I), is shown (n = 15 rAAV9.DSS-Nter-Ctrl mice, n = 17 rAAV9.DSS-Nter-shSost mice). Anxiety and depression behaviors, including the distance traveled in the central area (J) and the time spent in the central area (K) (n = 15 rAAV9.DSS-Nter-Ctrl mice, n = 17 rAAV9.DSS-Nter-shSost mice). L. Analysis of synaptic plasticity by measurement of average LTP are shown (n = 8 brain slices from rAAV9.DSS-Nter-Ctrl mice, n = 8 brain slices from rAAV9.DSS-Nter-shSost mice). M. The numbers of c-Fos-positive cells in the dentate gyrus of the hippocampus by immunohistochemical staining (n = 15 brain slices from rAAV9.DSS-Nter-Ctrl mice, n = 17 brain slices from rAAV9.DSS-Nter-shSost mice). N-R. Western blot (N) and the grey value analysis (O-R) for the β-catenin and synaptic markers in both the cortex and hippocampus (n = 3 biological samples for each group). S-T. Golgi staining and analysis of apical and basal dendritic spines in the cortex and hippocampus. (n = 20 brain slices from aged mice for each group). Notes: Data are represented as mean ± SEM. One-way ANOVA test followed by Turkey’s multiple comparisons test (B). Two-tailed unpaired t-test (D, F, G, H, I, J, K, L, M, O, P, Q, R, S, T).

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Extended Data Fig. 7 Sclerostin accelerates Αβ production via the Lrp6/β-catenin/BACE1 pathway.

A. The Evans blue staining and analysis (n = 3 biological samples for SOST-Tg and Sost-cKO experiments, n = 4 biological samples for SOST-KI experiments). B. The western blots for the integrity markers of the blood-brain barrier (n = 3 biological samples). C. The western blots analysis for the β-catenin and BACE1 levels in cortex and hippocampus from 18-month-old male Sost-cKO and WT mice (n = 3 biological samples for each group). D. The western blots analysis for the β-catenin and BACE1 levels in cortex and hippocampus from 6-month-old male SOST-KI and WT mice (n = 3 biological samples for each group). E. The western blots analysis for the β-catenin and BACE1 levels in cortex and hippocampus from aged female Sost-KO and WT mice (n = 3 biological samples for each group). F. The western blots analysis for the β-catenin and BACE1 levels in cortex and hippocampus from 6-month-old female SOST-KI and WT mice (n = 3 biological samples for each group). G. Western blot and grey value analysis for the β-catenin after different concentrations of recombinant sclerostin treatment (n = 2 replicated experiments and n = 3 biological samples for each experiment). H-I. Western blot analysis of p-GSK-3β expression in N2a cells after r-sclerostin (200 ng/ml) treatment for 3 hours (2 replicated experiments of 2 biological replicates). J. Western blot analysis of β-catenin and BACE1 levels in mouse neuroblastoma cells (N2a cells) after treatment with r-sclerostin (200 ng/ml) for 48 hours. K. Q-PCR analysis of Bace1 mRNA expression in N2a cells at 24 hours after treatment with r-sclerostin (200 ng/ml) with or without 2 μM BIO treatment (n = 9 biological samples). Notes: Data are represented as mean ± SEM. One-way ANOVA followed by Turkey’s multiple comparisons test (G, K). Two-tailed unpaired t-test (A, I). The grey value analysis of western blots can be seen in Supplemental Fig. 5.

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Extended Data Fig. 8 Increased osteocyte-derived sclerostin secretion accelerates Αβ production and cognitive decline in AD model mice.

A. The grey value analysis of western blot for β-catenin and BACE1 levels in cortical and hippocampal tissues (n = 4 biological samples). B. Aβ40 and Aβ42 concentrations in RIPA buffer-dissolved cortical and hippocampal tissues from APP/PS1 mice and WT mice after tail vein injection of rAAV9-DSS-Nter-Sost or rAAV9-DSS-Nter-Ctrl (n = 5 WT-Ctrl mice, n = 5 WT-Pla mice, n = 6 AD-Ctrl mice, n = 6 AD-Pla mice). C. The number of platform quadrant crossings in the MWM test is shown (n = 11 WT-Ctrl mice, n = 9 WT-Pla mice, n = 19 AD-Ctrl mice, n = 18 AD-Pla mice). D. Exploration of the novel object in the NOR test (n = 11 WT-Ctrl mice, n = 9 WT-Pla mice, n = 18 AD-Ctrl mice, n = 18 AD-Pla mice). Representative heat maps of the mice indicating exploration for the open field test, familiarization session and test session. E. Step-down latency in the IAT (n = 11 WT-Ctrl mice, n = 9 WT-Pla mice, n = 18 AD-Ctrl mice, n = 18 AD-Pla mice). F-G. Athletic ability, anxiety and depression were assessed by the open field test (n = 11 WT-Ctrl mice, n = 9 WT-Pla mice, n = 18 AD-Ctrl mice, n = 18 AD-Pla mice). Athletic ability, including the average speed (F). Anxiety and depression behaviors, including the time spent in the central area and distance traveled in the central area (G). H-I. Representative immunohistochemical staining images (H) and analysis (I) of c-Fos-positive cells in the hippocampus (n = 13 and 12 brain slides from AD-Ctrl and AD-Pla groups). J. Assessment of deficits in synaptic integrity by western blot analysis in the cortex and hippocampus (n = 3 biological samples for each group). Notes: WT-Ctrl: WT mice injected with rAAV9-DSS-Nter-Ctrl; WT-Pla: WT mice injected with rAAV9-DSS-Nter-Sost; AD-Ctrl: APP/PS1 AD mice injected with rAAV9-DSS-Nter-Ctrl; AD-Pla: APP/PS1 AD mice injected with rAAV9-DSS-Nter-Sost; MWM: Morris water maze. Data are represented as mean ± SEM. Box plots (B): the boundary of the box indicates the 25th and 75th percentile and the line within the box marks the median. Whiskers (error bars) above and below the box indicate the max and min percentiles. One-way ANOVA followed by Turkey’s multiple comparisons test (A, B, C, E, F, G). Two-tailed unpaired t-test (I).

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Extended Data Fig. 9 Scl-Ab alleviates memory impairment in AD mice with high serum sclerostin levels.

A. MicroCT analysis of the spongiosa of the femoral metaphysis. Quantification of the trabecular BS/BV, Tb.N, Tb.Sp, and Tb.Th (n = 8 WT-Ctrl mice, n = 8 AD-Ctrl mice, n = 8 AD rAAV-Sost mice, n = 6 AD rAAV-Sost+Scl-Ab mice). B. The levels of serum ALPL, Ocn, P1NP in mice from different groups (n = 5 WT-Ctrl mice, n = 5 AD-Ctrl mice, n = 4 AD rAAV-Sost mice, n = 5 AD rAAV-Sost+Scl-Ab mice). C. The protein levels of BACE1 and β-catenin in the cortex and hippocampus (2 biological replicates). D. Immunohistochemical staining for BACE1. E. Immunohistochemical staining for amyloid plaques using monoclonal anti-Aβ peptide (MOAB2) antibody. F-G. Analysis of athletic ability, anxiety and depression. Representative heat maps of the mice (F). Analysis of athletic ability, anxiety and depression, including the average speed, the time spent in the central area and the distance traveled in the central area (G) (n = 12 WT-Ctrl mice, n = 12 AD-Ctrl mice, n = 12 AD rAAV-Sost mice, n = 13 AD rAAV-Sost + Scl-Ab mice). H. The grey value analysis for the level of PSD95 and Syn in both cortex and hippocampus. Notes: WT-Ctrl: WT mice injected with rAAV9-DSS-Nter-Ctrl; AD-Ctrl: APP/PS1 mice injected with rAAV9-DSS-Nter-Ctrl; AD rAAV-Sost: APP/PS1 mice injected with rAAV9-DSS-Nter-Sost; AD rAAV-Sost+Scl-Ab: APP/PS1 mice injected with rAAV9-DSS-Nter-Sost and treated with Scl-Ab. Data are represented as mean ± SEM. One-way ANOVA followed by Turkey’s multiple comparisons test (A, B, G, H).

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Extended Data Table 1 The association between serum sclerostin and cognitive function in aged individuals
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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–6 and Tables 1–3 and unprocessed western blots for Supplementary Figs. 1, 2, 4 and 6.

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Supplementary Data

Supporting statistical data for Supplementary Figures.

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Shi, T., Shen, S., Shi, Y. et al. Osteocyte-derived sclerostin impairs cognitive function during ageing and Alzheimer’s disease progression. Nat Metab 6, 531–549 (2024). https://doi.org/10.1038/s42255-024-00989-x

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