Analysis of the functional relationship between NCAM2 and BACE1

Abstract

The neural cell adhesion molecule 2 (NCAM2) is a cell adhesion molecule (CAM) of the immunoglobulin superfamily (IgCAMs). NCAM2 plays an important role in the developing and mature nervous system by regulating neurite outgrowth and synapse formation and maintenance. NCAM2 is also involved in neurodevelopmental and neurodegenerative brain disorders, such as autism spectrum disorder (ASD) and Alzheimer’s disease (AD), respectively. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartic protease, which plays a key role in AD by cleaving the amyloid precursor protein (APP) to produce the toxic Aβ peptide accumulating in brains of AD patients. Synaptic levels of NCAM2 are reduced in the hippocampus of AD patients and Aβ treated cultured hippocampal neurons. Since BACE1 activity is increased in brains of AD patients, we investigated whether there is a functional interaction between NCAM2 and BACE1. Our study shows that NCAM2 can be cleaved by BACE1 and BACE2, a homolog of BACE1. The cleavage site of NCAM2 by BACE1 and BACE2 is within the extracellular domain region, which is close to the transmembrane domain of NCAM2. The intracellular domain of NCAM2 is not required for the cleavage. Our study also shows that BACE-dependent cleavage of NCAM2 is not enhanced by Aβ. The BACE-dependent turnover of NCAM2 is higher in hippocampal than in cortical neurons possibly due to higher exo- and endocytosis of BACE1 in hippocampal neurons when compared to cortical neurons. We also found that the cell surface levels of BACE1 and the shedding of BACE1 are increased in NCAM2 knock-out neurons, whereas the total levels and endocytosis of BACE1 are not affected by NCAM2 deficiency. Taken together, our study demonstrates that NCAM2 is cleaved by BACE1 and BACE2 and regulates cell surface levels of BACE1 most likely by regulating the delivery of BACE1 to the cell surface.