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Blood cell-produced amyloid-β induces cerebral Alzheimer-type pathologies and behavioral deficits

Molecular Psychiatry volume 26, pages 5568–5577 (2021)Cite this article

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Abstract

It is traditionally believed that cerebral amyloid-beta (Aβ) deposits are derived from the brain itself in Alzheimer’s disease (AD). Peripheral cells such as blood cells also produce Aβ. The role of peripherally produced Aβ in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aβ to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aβ in the blood, and caused AD phenotypes including Aβ plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aβ levels, and alleviated brain Aβ burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aβ plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aβ can decrease brain Aβ deposition and represents a novel therapeutic approach for AD.

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Fig. 1: Blood Aβ levels in wild-type (Wt) mice transplanted with APP/PS1-BMCs.
Fig. 2: Brain Aβ deposition and cerebral amyloid angiopathy (CAA) in wild-type (Wt) mice at 12 months after transplanting with APP/PS1-BMCs.
Fig. 3: Brain AD-type pathologies in wild-type (Wt) mice at 12 months after transplanting with APP/PS1-BMCs.
Fig. 4: Behavioral deficits in wild-type (Wt) mice at 12 months after transplanting with APP/PS1-BMCs.
Fig. 5: Bone marrow reconstitution with Wt-BMCs attenuated brain Aβ deposition, neuroinflammation, and neurodegeneration in APP/PS1 mice at 12 months after BMT.

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References

  1. Gao Y, Liu Q, Xu L, Zheng N, He X, Xu F. Imaging and spectral characteristics of amyloid plaque autofluorescence in brain slices from the APP/PS1 mouse model of Alzheimer’s disease. Neurosci Bull. 2019;35:1126–37.

    PubMed  PubMed Central  Google Scholar 

  2. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 1995;375:754–60.

    CAS  PubMed  Google Scholar 

  3. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature. 1995;376:775–8.

    CAS  PubMed  Google Scholar 

  4. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349:704–6.

    CAS  PubMed  Google Scholar 

  5. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488:96–9.

    CAS  PubMed  Google Scholar 

  6. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci USA. 1994;91:11993–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen M, Inestrosa NC, Ross GS, Fernandez HL. Platelets are the primary source of amyloid beta-peptide in human blood. Biochem Biophys Res Commun. 1995;213:96–103.

    CAS  PubMed  Google Scholar 

  9. Kuo YM, Kokjohn TA, Watson MD, Woods AS, Cotter RJ, Sue LI, et al. Elevated abeta42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbetaPP metabolism. Am J Pathol. 2000;156:797–805.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Davies TA, Long HJ, Eisenhauer PB, Hastey R, Cribbs DH, Fine RE, et al. Beta amyloid fragments derived from activated platelets deposit in cerebrovascular endothelium: usage of a novel blood brain barrier endothelial cell model system. Amyloid. 2000;7:153–65.

    CAS  PubMed  Google Scholar 

  11. Roher AE, Esh CL, Kokjohn TA, Castano EM, Van Vickle GD, Kalback WM, et al. Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer’s disease. Alzheimers Dement. 2009;5:18–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Li S, Liu B, Zhang L, Rong L. Amyloid beta peptide is elevated in osteoporotic bone tissues and enhances osteoclast function. Bone. 2014;61:164–75.

    CAS  PubMed  Google Scholar 

  13. Van Nostrand WE, Melchor JP. Disruption of pathologic amyloid beta-protein fibril assembly on the surface of cultured human cerebrovascular smooth muscle cells. Amyloid. 2001;8 Suppl 1:20–7.

    PubMed  Google Scholar 

  14. Starke R, Harrison P, Mackie I, Wang G, Erusalimsky JD, Gale R, et al. The expression of prion protein (PrP(C)) in the megakaryocyte lineage. J Thromb Haemost. 2005;3:1266–73.

    CAS  PubMed  Google Scholar 

  15. Kemp KC, Dey R, Verhagen J, Scolding NJ, Usowicz MM, Wilkins A. Aberrant cerebellar Purkinje cell function repaired in vivo by fusion with infiltrating bone marrow-derived cells. Acta Neuropathol. 2018;135:907–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Shen LL, Manucat-Tan NB, Gao SH, Li WW, Zeng F, Zhu C, et al. The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau. Mol Psychiatry. 2018;23:1813–24.

    CAS  PubMed  Google Scholar 

  17. Xiang Y, Bu XL, Liu YH, Zhu C, Shen LL, Jiao SS, et al. Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer’s disease. Acta Neuropathol. 2015;130:487–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Jin WS, Shen LL, Bu XL, Zhang WW, Chen SH, Huang ZL, et al. Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model. Acta Neuropathol. 2017;134:207–20.

    CAS  PubMed  Google Scholar 

  19. Fukuchi K, Ho L, Younkin SG, Kunkel DD, Ogburn CE, LeBoeuf RC, et al. High levels of circulating beta-amyloid peptide do not cause cerebral beta-amyloidosis in transgenic mice. Am J Pathol. 1996;149:219–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bu XL, Xiang Y, Jin WS, Wang J, Shen LL, Huang ZL, et al. Blood-derived amyloid-beta protein induces Alzheimer’s disease pathologies. Mol Psychiatry. 2018;23:1–9.

    Google Scholar 

  21. Eisele YS, Obermuller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010;330:980–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Eisele YS, Fritschi SK, Hamaguchi T, Obermuller U, Fuger P, Skodras A, et al. Multiple factors contribute to the peripheral induction of cerebral beta-amyloidosis. J Neurosci. 2014;34:10264–73.

    PubMed  PubMed Central  Google Scholar 

  23. Burwinkel M, Lutzenberger M, Heppner FL, Schulz-Schaeffer W, Baier M. Intravenous injection of beta-amyloid seeds promotes cerebral amyloid angiopathy (CAA). Acta Neuropathol Commun. 2018;6:23.

    PubMed  PubMed Central  Google Scholar 

  24. Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020;581:71–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bigg M. Forensics find donor DNA in semen of bone marrow transplant patient. 2019. https://www.bionews.org.uk/page_146800.

  26. Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, et al. Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature. 2015;525:247–50.

    CAS  PubMed  Google Scholar 

  27. Duyckaerts C, Sazdovitch V, Ando K, Seilhean D, Privat N, Yilmaz Z, et al. Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology. Acta Neuropathol. 2018;135:201–12.

    CAS  PubMed  Google Scholar 

  28. Ritchie DL, Adlard P, Peden AH, Lowrie S, Le Grice M, Burns K, et al. Amyloid-beta accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol. 2017;134:221–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kozin SA, Cheglakov IB, Ovsepyan AA, Telegin GB, Tsvetkov PO, Lisitsa AV, et al. Peripherally applied synthetic peptide isoAsp7-Abeta(1-42) triggers cerebral beta-amyloidosis. Neurotox Res. 2013;24:370–6.

    CAS  PubMed  Google Scholar 

  30. Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013;501:45–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris JC, Beekly D, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology. 1996;46:1592–6.

    CAS  PubMed  Google Scholar 

  32. Brenowitz WD, Nelson PT, Besser LM, Heller KB, Kukull WA. Cerebral amyloid angiopathy and its co-occurrence with Alzheimer’s disease and other cerebrovascular neuropathologic changes. Neurobiol Aging. 2015;36:2702–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, et al. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci. 2004;7:954–60.

    CAS  PubMed  Google Scholar 

  34. Cheng X, He P, Yao H, Dong Q, Li R, Shen Y. Occludin deficiency with BACE1 elevation in cerebral amyloid angiopathy. Neurology. 2014;82:1707–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Edgren G, Hjalgrim H, Rostgaard K, Lambert P, Wikman A, Norda R, et al. Transmission of neurodegenerative disorders through blood transfusion: a cohort study. Ann Intern Med. 2016;165:316–24.

    PubMed  Google Scholar 

  36. Lin SY, Hsu WH, Lin CC, Lin CL, Yeh HC, Kao CH. Association of transfusion with risks of dementia or Alzheimer’s disease: a population-based cohort study. Front Psychiatry. 2019;10:571.

    PubMed  PubMed Central  Google Scholar 

  37. Bu XL, Li WW, Wang YJ. Is Alzheimer’s disease transmissible in humans? Neurosci Bull. 2019;35:1113–5.

    PubMed  PubMed Central  Google Scholar 

  38. Middeldorp J, Lehallier B, Villeda SA, Miedema SS, Evans E, Czirr E, et al. Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol. 2016;73:1325–33.

    PubMed  PubMed Central  Google Scholar 

  39. Nilsson LN, Gografe S, Costa DA, Hughes T, Dressler D, Potter H. Use of fused circulations to investigate the role of apolipoprotein E as amyloid catalyst and peripheral sink in Alzheimer’s disease. Technol Innov. 2012;14:199–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20:659–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477:90–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang J, Gu BJ, Masters CL, Wang YJ. A systemic view of Alzheimer disease—insights from amyloid-beta metabolism beyond the brain. Nat Rev Neurol. 2017;13:612–23.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by National Natural Science Foundation of China (81930028, 81625007, 91749206, 81701043, and 31921003).

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Authors and Affiliations

  1. Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China

    Hao-Lun Sun, Si-Han Chen, Zhong-Yuan Yu, Yuan Cheng, Ding-Yuan Tian, Dong-Yu Fan, Chen-Yang He, Jun Wang, Pu-Yang Sun, Yang Chen, Cheng-Rong Tan, Hua-Dong Zhou, Xian-Le Bu & Yan-Jiang Wang

  2. Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China

    Hao-Lun Sun, Si-Han Chen, Zhong-Yuan Yu, Yuan Cheng, Ding-Yuan Tian, Dong-Yu Fan, Chen-Yang He, Jun Wang, Pu-Yang Sun, Yang Chen, Cheng-Rong Tan, Hua-Dong Zhou, Xiao-Wei Chen, Zhi-An Hu, Xian-Le Bu & Yan-Jiang Wang

  3. Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China

    Hao-Lun Sun, Si-Han Chen, Zhong-Yuan Yu, Yuan Cheng, Ding-Yuan Tian, Dong-Yu Fan, Chen-Yang He, Jun Wang, Pu-Yang Sun, Yang Chen, Cheng-Rong Tan, Hua-Dong Zhou, Xian-Le Bu & Yan-Jiang Wang

  4. State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China

    Jun-Ping Wang

  5. Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada

    Weihong Song

  6. Brain Research Center, Third Military Medical University, Chongqing, China

    Xiao-Wei Chen

  7. Department of Physiology, Third Military Medical University, Chongqing, China

    Zhi-An Hu

  8. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Yan-Jiang Wang

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  1. Hao-Lun Sun
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Contributions

YJW and XLB conceived and designed the project, JPW provided technical assistance for BMT, SHC, ZYY, YC, DYT, DYF, CYH, JW, PYS, and CRT conducted animal and in vitro experiments, HLS, XLB, and YJW analyzed data. YC, XWC, ZAH, WHS, and HDZ critically read and revised the paper, XLB and YJW wrote the paper.

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Correspondence to Xian-Le Bu or Yan-Jiang Wang.

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Sun, HL., Chen, SH., Yu, ZY. et al. Blood cell-produced amyloid-β induces cerebral Alzheimer-type pathologies and behavioral deficits. Mol Psychiatry 26, 5568–5577 (2021). https://doi.org/10.1038/s41380-020-0842-1

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