title: Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model.
abstract: BACKGROUND
  CD2-associated protein (CD2AP) is an SH3-containing scaffold adaptor protein which regulates the actin cytoskeleton. Recently, CD2AP was identified as a genetic risk factor for Alzheimer's disease (AD) by several genome-wide association studies. One of the hallmarks of AD is the accumulation of aggregated forms of Amyloid-β (Aβ) in the brain. In humans, CD2AP AD susceptibility locus (rs9349407) is associated with an increased plaque burden. Aβ production is highly regulated by endocytosis and is influenced by lysosomal function. Lysosomal trafficking is influenced by CD2AP. In this study, we decreased CD2AP levels in N2a neuroblastoma cultures and PS1APP mice and analyzed Aβ levels and plaque burden.
  
  
  RESULTS
  Our data show that suppressing CD2AP expression using shRNA in N2a-APP695 cells results in decreased cell membrane amyloid precursor protein, decreased Aβ release and a lower Aβ42/Aβ40 ratio. CD2AP protein is expressed in the brain as detected by western blot, and the expression level is dependent on gene dosage. In 1-month old PS1APP mice, complete loss of CD2AP in brain resulted in a decreased Aβ42/Aβ40 ratio in brain tissue lysates while there was no effect on Aβ deposition or accumulation in PS1APP mice expressing one copy of CD2AP.
  
  
  CONCLUSIONS
  CD2-Associated Protein affects Aβ levels and Aβ42/Aβ40 ratio in vitro. The effect of CD2-Associated Protein on Aβ metabolism is subtle in vivo.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. liaof@neuro.wustl.edu.
authors.forename: Fan
authors.initials: F
authors.lastname: Liao
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. jianh@neuro.wustl.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. shuba0112@gmail.com.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Srivatsan
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. xiaoq@neuro.wustl.edu.
authors.forename: Qingli
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. klefton@bu.edu.
authors.forename: Katheryn B
authors.initials: KB
authors.lastname: Lefton
authors.affiliation: Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. yamadaka@m.u-tokyo.ac.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. mahant@wustl.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mahan
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. leejm@neuro.wustl.edu.
authors.forename: Jin-Moo
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. shaw@pathology.wustl.edu.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. holtzman@neuro.wustl.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D055106:Genome-Wide Association Study; D006801:Humans; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D053829:Amyloid Precursor Protein Secretases