CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk
Abstract
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.
Article Details
Authors (50)
Roger B. Dodd
Masahiro Enomoto
Ye Zhou
Kanayo Satoh
Yalun Zhang
Fusheng Chen
Beatrice Acheson
Deniz Ghaffari
Elizabeth Sayn-Wittgenstein
Jamie J. Manning
George V. Dukas
Ronak Patel
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
Alondra Schweizer Burguete
Mason J. Kralovec
Mamunur Rashid
Jennifer L. Hall
Kirstin A. Tamucci
Zena Chatila
Minghua Liu
CAS Key Laboratory of Colloid, Interface and Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, No. 2 North First Street, Zhongguancun, Beijing 100190, China
Annie J. Lee
Badri N. Vardarajan
Mariko F. Taga
Sirkku Pollari
Alon Rabinovitch
Cory D. Rillahan
Andrey A. Bobkov
Eduard Sergienko
William Meadows
Seema Qamar
Suzanne J. Randle
Christopher M. Johnson
Jean Sevalle
Jennifer Griffin
Christopher Bohm
Mitsuhiko Ikura
Xunde Xian
Joachim Herz
Department of Neurology, University of Texas Southwestern Medical Center
Megan A. Kelly
Jennifer West
Sandeep Satapathy
Mark R. Wilson
Department of Chemistry, Durham University, South Road, Durham DH1 3LE, U.K.
Jonathan A. Javitch
Paul E. Fraser
David A. Bennett
Philip L. De Jager
Zvi Fishelson
Dan Frenkel
The School of Neurobiology, Biochemistry, and Biophysics George S. Wise Faculty of Life Sciences, Tel Aviv University
Wesley B. Asher
Elizabeth M. Bradshaw
Peter St George-Hyslop