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Cited by 53Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model

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Liao, Fan, Jiang, Hong, Srivatsan, Subhashini, Xiao, Qingli, Lefton, Katheryn B, Yamada, Kaoru, Mahan, Thomas E, Lee, Jin-Moo +2 more·2015·Molecular Neurodegeneration
DOI 10.1186/s13024-015-0006-yPMC PMC4374406
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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. CONCLUSION: 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.

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Authors
Liao, F., Jiang, H., Srivatsan, S., Xiao, Q., Lefton, K. B., Yamada, K., Mahan, T. E., Lee, J.-M., Shaw, A. S., & Holtzman, D. M.
Affiliations
  • Washington University in St. Louis (US)
  • The University of Tokyo (JP)
Corresponding author
Holtzman, David M
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2015-03-19
Volume
10
Issue
1
Pages
12-12
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-015-0006-y
PMC
PMC4374406
OpenAlex
W2162151621
Cited by
53
References
6
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 5 · 2015: 2
FWCI
3.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • JPB Foundation
  • Cure Alzheimer's Fund
  • National Institutes of Health (NINDS R21)
  • National Institute of Allergy and Infectious Diseases (AI57966, R37AI057966)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK96688)
  • National Institute of Neurological Disorders and Stroke (R21NS082529, R01NS067905, R01NS048283)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
CD2AP, amyloid-beta, Alzheimer's disease, APP695, neuroblastoma cells, actin cytoskeleton, lysosomal trafficking, endocytosis, gene dosage, shRNA knockdown
MeSH terms
Alzheimer Disease, Animals, Brain, Cytoskeletal Proteins, Disease Models, Animal, Humans, Mice, Transgenic, Neuroblastoma, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Adaptor Proteins, Signal Transducing, Amyloid Precursor Protein Secretases, Genome-Wide Association Study

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