Galectin 3–binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein

Alzheimer's disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of ?-amyloid (A?) peptides. A? is produced from amyloid precursor protein (APP) that is sequentially cleaved by ?- and ?-secretases. Therefore, APP processing has been a target in therapeutic strategies for managing AD; however, no effective treatment of AD patients is currently available. Here, to identify endogenous factors that modulate A? production, we performed a gene microarray?based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because A? production in these cells changes during neuronal differentiation. We found that expression of the glycophosphatidylinositol-specific phospholipase D1 (GPLD1) gene is associated with these changes in A? production. GPLD1 overexpression in HEK293 cells increased the secretion of galectin 3?binding protein (GAL3BP), which suppressed A? production in an AD model, neuroglioma H4 cells. Mechanistically, GAL3BP suppressed A? production by directly interacting with APP and thereby inhibiting APP processing by ?-secretase. Furthermore, we show that cells take up extracellularly added GAL3BP via endocytosis and that GAL3BP is localized in close proximity to APP in endosomes where amyloidogenic APP processing takes place. Taken together, our results indicate that GAL3BP may be a suitable target of AD-modifying drugs in future therapeutic strategies for managing AD.