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

Molecular neurodegeneration

PubMedID: 25887956

Liao F, Jiang H, Srivatsan S, Xiao Q, Lefton KB, Yamada K, Mahan TE, Lee JM, Shaw AS, Holtzman DM. Effects of CD2-associated protein deficiency on amyloid-ß in neuroblastoma cells and in an APP transgenic mouse model. Mol Neurodegener. 2015;10(1):12.
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-ß (Aß) in the brain. In humans, CD2AP AD susceptibility locus (rs9349407) is associated with an increased plaque burden. Aß 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 Aß 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 Aß release and a lower Aß42/Aß40 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 Aß42/Aß40 ratio in brain tissue lysates while there was no effect on Aß deposition or accumulation in PS1APP mice expressing one copy of CD2AP.

CONCLUSION
CD2-Associated Protein affects Aß levels and Aß42/Aß40 ratio in vitro. The effect of CD2-Associated Protein on Aß metabolism is subtle in vivo.