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CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology

Nature Neuroscience volume 16, pages 848–850 (2013)Cite this article

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Abstract

In our functional dissection of the CD33 Alzheimer's disease susceptibility locus, we found that the rs3865444C risk allele was associated with greater cell surface expression of CD33 in the monocytes (t50 = 10.06, Pjoint = 1.3 × 10−13) of young and older individuals. It was also associated with diminished internalization of amyloid-β 42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of activated human microglia.

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Figure 1: The CD33 risk allele is associated with increased CD33 expression and decreased uptake.
Figure 2: The rs3865444 allele is associated with an increase in PiB imaging.
Figure 3: Immunohistochemistry reveals CD33 expression in the brain and an increase frequency of stage III microglia/macrophages associated with rs3865444C.

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References

  1. Harold, D. et al. Nat. Genet. 41, 1088–1093 (2009).

    Article  CAS  Google Scholar 

  2. Lambert, J.C. et al. Nat. Genet. 41, 1094–1099 (2009).

    Article  CAS  Google Scholar 

  3. Seshadri, S. et al. J. Am. Med. Assoc. 303, 1832–1840 (2010).

    Article  CAS  Google Scholar 

  4. Hollingworth, P. et al. Nat. Genet. 43, 429–435 (2011).

    Article  CAS  Google Scholar 

  5. Naj, A.C. et al. Nat. Genet. 43, 436–441 (2011).

    Article  CAS  Google Scholar 

  6. Hollingworth, P., Harold, D., Jones, L., Owen, M.J. & Williams, J. Int. J. Geriatr. Psychiatry 26, 793–802 (2011).

    Article  Google Scholar 

  7. Carrasquillo, M.M. et al. Mol. Neurodegener. 6, 54 (2011).

    Article  CAS  Google Scholar 

  8. Karch, C.M. et al. PLoS ONE 7, e50976 (2012).

    Article  CAS  Google Scholar 

  9. Griciuc, A. et al. Neuron published online, doi:10.1016/j.neuron.2013.04.014 (23 April 2013).

  10. Lajaunias, F., Dayer, J.M. & Chizzolini, C. Eur. J. Immunol. 35, 243–251 (2005).

    Article  CAS  Google Scholar 

  11. Bennett, D.A. et al. Curr. Alzheimer Res. 9, 646–663 (2012).

    Article  CAS  Google Scholar 

  12. Bennett, D.A., Schneider, J.A., Arvanitakis, Z. & Wilson, R.S. Curr Alzheimer Res. 9, 628–645 (2012).

    Article  CAS  Google Scholar 

  13. Bienias, J.L., Beckett, L.A., Bennett, D.A., Wilson, R.S. & Evans, D.A. J. Alzheimers Dis. 5, 349–355 (2003).

    Article  Google Scholar 

  14. Fiala, M., Cribbs, D.H., Rosenthal, M. & Bernard, G. J. Alzheimers Dis. 11, 457–463 (2007).

    Article  CAS  Google Scholar 

  15. Okello, A. et al. Neurology 73, 754–760 (2009).

    Article  CAS  Google Scholar 

  16. Mackenzie, I.R. Neurology 55, 132–134 (2000).

    Article  CAS  Google Scholar 

  17. Sperling, R.A. et al. Alzheimers Dement. 7, 280–292 (2011).

    Article  Google Scholar 

  18. Sperling, R.A., Jack, C.R. Jr. & Aisen, P.S. Sci. Transl. Med. 3, 111cm133 (2011).

    Article  Google Scholar 

  19. Salloway, S. et al. Neurology 73, 2061–2070 (2009).

    Article  CAS  Google Scholar 

  20. Winblad, B. et al. Lancet Neurol. 11, 597–604 (2012).

    Article  CAS  Google Scholar 

  21. Morris, J.C. Neurology 43, 2412–2414 (1993).

    Article  CAS  Google Scholar 

  22. Wechsler, D. Wechsler Memory Scale-Revised (WMS-R) (Psychological, San Antonio, Texas, 1987).

    Google Scholar 

  23. Folstein, M.F., Folstein, S.E. & McHugh, P.R. J. Psychiatr. Res. 12, 189–198 (1975).

    Article  CAS  Google Scholar 

  24. Yesavage, J.A. et al. J. Psychiatr. Res. 17, 37–49 (1982).

    Article  Google Scholar 

  25. Price, A.L. et al. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  26. Ciaramella, A., et al. J. Alzheimers Dis. 19, 559–572 (2010).

    Article  Google Scholar 

  27. Bennett, D.A. et al. Neurology 66, 1837–1844 (2006).

    Article  CAS  Google Scholar 

  28. Bennett, D.A., Schneider, J.A., Bienias, J.L., Evans, D.A. & Wilson, R.S. Neurology 64, 834–841 (2005).

    Article  CAS  Google Scholar 

  29. Schneider, J.A., Wilson, R.S., Bienias, J.L., Evans, D.A. & Bennett, D.A. Neurology 62, 1148–1155 (2004).

    Article  CAS  Google Scholar 

  30. Anonymous. Neurobiol. Aging 18, S1–S2 (1997).

  31. Mathis, C.A. et al. J. Med. Chem. 46, 2740–2754 (2003).

    Article  CAS  Google Scholar 

  32. Klunk, W.E. et al. Ann. Neurol. 55, 306–319 (2004).

    Article  CAS  Google Scholar 

  33. Gomperts, S.N. et al. Neurology 71, 903–910 (2008).

    Article  CAS  Google Scholar 

  34. Hedden, T. et al. J. Neurosci. 29, 12686–12694 (2009).

    Article  CAS  Google Scholar 

  35. Logan, J. et al. J. Cereb. Blood Flow Metab. 10, 740–747 (1990).

    Article  CAS  Google Scholar 

  36. Price, J.C. et al. J. Cereb. Blood Flow Metab. 25, 1528–1547 (2005).

    Article  CAS  Google Scholar 

  37. Lopresti, B.J. et al. J. Nucl. Med. 46, 1959–1972 (2005).

    CAS  PubMed  Google Scholar 

  38. Fagan, A.M. et al. Ann. Neurol. 59, 512–519 (2006).

    Article  CAS  Google Scholar 

  39. Johnson, K.A. et al. Ann. Neurol. 62, 229–234 (2007).

    Article  Google Scholar 

  40. Johnson, W.E., Li, C. & Rabinovic, A. Biostatistics 8, 118–127 (2007).

    Article  Google Scholar 

  41. Reich, M. et al. Nat. Genet. 38, 500–501 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the participants of the ROS, MAP, CHAP, Harvard Aging Brain Study (HAB) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. Data used in preparation of this article were obtained from the ADNI database (http://adni.loni.ucla.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. We also thank the participants of the Brigham and Women's PhenoGenetic Project. This work is supported by the US National Institutes of Health (grants R01 AG031553, R01 AG30146, R01 AG17917, R01 AG15819, P30 AG10161 and R01 AG11101) and the Illinois Department of Public Health. This work was supported by grants R01 NS067305, RC2 GM093080 and R01 AG043617. E.M.B. receives support from the JDRF, American Diabetes Association, Boston Area Diabetes and Endocrinology Research Center and the Harvard NeuroDiscovery Center.

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Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Elizabeth M Bradshaw, Lori B Chibnik, Brendan T Keenan, Linda Ottoboni, Towfique Raj, Anna Tang, Laura L Rosenkrantz, Selina Imboywa, Michelle Lee, Alina Von Korff & Philip L De Jager

  2. Department of Neurology, Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Elizabeth M Bradshaw, Lori B Chibnik, Brendan T Keenan, Linda Ottoboni, Towfique Raj, Anna Tang, Laura L Rosenkrantz, Selina Imboywa, Michelle Lee & Alina Von Korff

  3. Harvard Medical School, Boston, Massachusetts, USA

    Elizabeth M Bradshaw, Lori B Chibnik, Linda Ottoboni, Towfique Raj, Keith Johnson & Reisa A Sperling

  4. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA

    Elizabeth M Bradshaw, Lori B Chibnik, Brendan T Keenan, Linda Ottoboni, Towfique Raj, Anna Tang, Laura L Rosenkrantz, Selina Imboywa & Philip L De Jager

  5. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA

    Martha C Morris, Julie A Schneider & David A Bennett

  6. Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois, USA

    Denis A Evans

  7. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Keith Johnson & Reisa A Sperling

  8. Department of Neurology, Center for Alzheimer's Research and Treatment, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Reisa A Sperling

  9. The Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts, USA

    Keith Johnson & Reisa A Sperling

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  1. Elizabeth M Bradshaw
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The Alzheimer Disease Neuroimaging Initiative

Contributions

E.M.B. and P.L.D. designed and implemented the study. E.M.B. developed the experimental methods using peripheral blood mononuclear cells (PBMCs). E.M.B., L.O., A.T., L.L.R. and S.I. isolated PBMCs from the PhenoGenetic cohort and analyzed monocyte CD33 expression. E.M.B., A.T. and L.L.R. analyzed the uptake ability of monocytes. T.R., B.T.K. and L.B.C. performed the statistical analyses and assisted with the interpretation and communication of results. A.V.K., M.L. and P.L.D. coordinated the collection of blood from the PhenoGenetic cohort. R.A.S., K.J. and ADNI provided the PiB imaging data and reviewed the manuscript. R.A.S. provided the HAB blood samples. M.C.M. contributed post-mortem data on brain microglia and reviewed the manuscript. D.A.E. provided clinical data and biospecimens. J.A.S. was responsible for the microglia and Alzheimer's disease pathology data collection from the brains of deceased MAP participants and revised the manuscript. D.A.B. contributed ante-mortem biospecimens, clinical and post-mortem data, and revised the manuscript. P.L.D. conceived the study, coordinated access to all of the cohorts and wrote the manuscript with E.M.B.

Corresponding author

Correspondence to Philip L De Jager.

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The authors declare no competing financial interests.

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A full list of members is available at http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

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Bradshaw, E., Chibnik, L., Keenan, B. et al. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16, 848–850 (2013). https://doi.org/10.1038/nn.3435

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