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Peer-reviewedCC BYNature Communications

CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk

  • Roger B. Dodd1,2
  • Masahiro Enomoto3,4,5
  • Ye Zhou6,7,8,9
  • Kanayo Satoh6,7,8,9
  • Yalun Zhang6,7,8,9
  • Fusheng Chen6,7,8,9
  • Beatrice Acheson6,7,8,9
  • Deniz Ghaffari6,7,8,9
  • Elizabeth Sayn-Wittgenstein6,7,8,9
  • Jamie J. Manning10,11,12,13
  • George V. Dukas10,11,12,13
  • Ronak B. Patel14,15
38 more authors
  • Alondra Schweizer Burguete14,15
  • Mason J. Kralovec14,15
  • Mamunur Rashid14,16,17
  • Jennifer L. Hall14,16,17
  • Kirstin A. Tamucci14,16,17
  • Zena K. Chatila14,16,15
  • Minghua Liu14,15
  • Annie Lee14,15
  • Badri Narayan Vardarajan14,15
  • Mariko F. Taga18,19
  • Sirkku Pollari20,21
  • Alon Rabinovich22,23
  • Cory D. Rillahan24,25
  • Andrey A. Bobkov20,21
  • Eduard A. Sergienko20,21
  • William Meadows1,2
  • Seema Qamar1,2
  • Suzanne J. Randle1,2
  • Christopher M. Johnson26,27
  • Jean Sévalle6,7,8,9
  • Jennifer K. Griffin6,7,8,9
  • Christopher Böhm6,7,8,9
  • Mitsuhiko Ikura3,4,5
  • Xunde Xian28,29,30
  • Joachim Herz28,29,30
  • Megan A. Kelly31,32
  • Jennifer West31,32
  • Sandeep Satapathy31,32
  • Mark R. Wilson31,32
  • Jonathan A. Javitch10,11,12,13
  • Paul Fraser3,7,8,9
  • David A. Bennett33
  • Philip L. De Jager18,19
  • Zvi Fishelson34,35
  • Dan Frenkel34,22,35
  • Wesley B. Asher36,37,12,13
  • Elizabeth M. Bradshaw38,39,17
  • Peter St George‐Hyslop40,2,15,8,9
40 affiliations
  1. 1Cambridge Institute for Medical Research, Cambridge, UK
  2. 2Cambridge Institute for Medical Research, Welcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom
  3. 3Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
  4. 4Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
  5. 5Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
  6. 6Department of Medicine (Division of Neurology), University Health Network, Toronto, ON, Canada
  7. 7Department of Medicine (Neurology), Tanz Centre for Research in Neurodegenerative Diseases, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
  8. 8Department of Medicine (Division of Neurology) and University Health Network, Toronto, ON, Canada
  9. 9Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine (Neurology) and Medical Biophysics, University of Toronto
  10. 10Department of Psychiatry and Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
  11. 11Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
  12. 12Department of Psychiatry and Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
  13. 13Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA
  14. 14Carol and Gene Ludwig Center for Research on Neurodegeneration, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
  15. 15Carol and Gene Ludwig Center for Research on Neurodegeneration, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Departments of Neurology Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA
  16. 16Division of Translational Neurobiology, Departments of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
  17. 17Division of Translational Neurobiology, Departments of Neurology Columbia University Medical Center, 30 West 18th Street, New York, NY 10032, USA
  18. 18Center for Translational and Computational Neuroimmunology, Departments of Neurology Columbia University Medical Center, New York, NY, USA
  19. 19Center for Translational and Computational Neuroimmunology, Departments of Neurology Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA
  20. 20Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
  21. 21Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037
  22. 22Department of Neurobiology, George S. Wise Faculty of Life Sciences, School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel
  23. 23Department of Neurobiology, George S. Wise Faculty of Life Sciences, School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv 678, Israel
  24. 24Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA
  25. 25Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 300 Longwood Avenue Boston, MA 02115, USA
  26. 26MRC Laboratory of Molecular Biology, Cambridge, UK
  27. 27MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 OQH, United Kingdom
  28. 28Department of Molecular Genetics, Center for Translational Neurodegeneration Research9, University of Texas Southwestern, Dallas, TX, USA
  29. 29Department of Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX, USA
  30. 30Departments of Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX 75390
  31. 31School of Science, Faculty of Science, Medicine & Health, Molecular Horizons Research Institute, University of Wollongong, Wollongong, NSW, Australia
  32. 32School of Science, Faculty of Science, Medicine & Health, Molecular Horizons Research Institute, University of Wollongong, Northfields Avenue, Wollongong. NSW. 2522. AUSTRALIA
  33. 33Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
  34. 34Department of Cell and Developmental Biology, Faculty of Medicine, and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
  35. 35Department of Cell and Developmental Biology, Faculty of Medicine, and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel
  36. 36Department of Psychiatry and Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. [email protected]
  37. 37Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA. [email protected]
  38. 38Carol and Gene Ludwig Center for Research on Neurodegeneration, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. [email protected]
  39. 39Division of Translational Neurobiology, Departments of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. [email protected]
  40. 40Cambridge Institute for Medical Research, Cambridge, UK. [email protected]
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Abstract

Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33 M splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33 M ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33 M , but not CD33 m . We show that in human monocytes CD33 M :CLU binding induces CD33 M ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33 M ectodomain fragment (sCD33 M ) - absent from CD33 m -expressing cells - which could contribute to the role of CD33 M in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33 M axis, highlighting CD33 M dimerization and ligand-binding sites as potential therapeutic targets.

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Cite

BibTeXRIS
BibTeX
@article{dodd2026cd33,
  title = {{CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk}},
  author = {Roger B. Dodd and Masahiro Enomoto and Ye Zhou and Kanayo Satoh and Yalun Zhang and Fusheng Chen and Beatrice Acheson and Deniz Ghaffari and Elizabeth Sayn-Wittgenstein and Jamie J. Manning and George V. Dukas and Ronak B. Patel and Alondra Schweizer Burguete and Mason J. Kralovec and Mamunur Rashid and Jennifer L. Hall and Kirstin A. Tamucci and Zena K. Chatila and Minghua Liu and Annie Lee and Badri Narayan Vardarajan and Mariko F. Taga and Sirkku Pollari and Alon Rabinovich and Cory D. Rillahan and Andrey A. Bobkov and Eduard A. Sergienko and William Meadows and Seema Qamar and Suzanne J. Randle and Christopher M. Johnson and Jean Sévalle and Jennifer K. Griffin and Christopher Böhm and Mitsuhiko Ikura and Xunde Xian and Joachim Herz and Megan A. Kelly and Jennifer West and Sandeep Satapathy and Mark R. Wilson and Jonathan A. Javitch and Paul Fraser and David A. Bennett and Philip L. De Jager and Zvi Fishelson and Dan Frenkel and Wesley B. Asher and Elizabeth M. Bradshaw and Peter St George‐Hyslop},
  journal = {Nature Communications},
  year = {2026},
  month = jul,
  doi = {10.1038/s41467-026-75140-3},
  url = {https://doi.org/10.1038/s41467-026-75140-3},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk
AU  - Roger B. Dodd
AU  - Masahiro Enomoto
AU  - Ye Zhou
AU  - Kanayo Satoh
AU  - Yalun Zhang
AU  - Fusheng Chen
AU  - Beatrice Acheson
AU  - Deniz Ghaffari
AU  - Elizabeth Sayn-Wittgenstein
AU  - Jamie J. Manning
AU  - George V. Dukas
AU  - Ronak B. Patel
AU  - Alondra Schweizer Burguete
AU  - Mason J. Kralovec
AU  - Mamunur Rashid
AU  - Jennifer L. Hall
AU  - Kirstin A. Tamucci
AU  - Zena K. Chatila
AU  - Minghua Liu
AU  - Annie Lee
AU  - Badri Narayan Vardarajan
AU  - Mariko F. Taga
AU  - Sirkku Pollari
AU  - Alon Rabinovich
AU  - Cory D. Rillahan
AU  - Andrey A. Bobkov
AU  - Eduard A. Sergienko
AU  - William Meadows
AU  - Seema Qamar
AU  - Suzanne J. Randle
AU  - Christopher M. Johnson
AU  - Jean Sévalle
AU  - Jennifer K. Griffin
AU  - Christopher Böhm
AU  - Mitsuhiko Ikura
AU  - Xunde Xian
AU  - Joachim Herz
AU  - Megan A. Kelly
AU  - Jennifer West
AU  - Sandeep Satapathy
AU  - Mark R. Wilson
AU  - Jonathan A. Javitch
AU  - Paul Fraser
AU  - David A. Bennett
AU  - Philip L. De Jager
AU  - Zvi Fishelson
AU  - Dan Frenkel
AU  - Wesley B. Asher
AU  - Elizabeth M. Bradshaw
AU  - Peter St George‐Hyslop
PY  - 2026
DA  - 2026/07/17
JO  - Nature Communications
DO  - 10.1038/s41467-026-75140-3
UR  - https://doi.org/10.1038/s41467-026-75140-3
AB  - Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33 M splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33 M ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33 M , but not CD33 m . We show that in human monocytes CD33 M :CLU binding induces CD33 M ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33 M ectodomain fragment (sCD33 M ) - absent from CD33 m -expressing cells - which could contribute to the role of CD33 M in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33 M axis, highlighting CD33 M dimerization and ligand-binding sites as potential therapeutic targets.
SN  - 2041-1723
ER  -