Abstract
Alzheimer's disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of β-amyloid (Aβ) peptides. Aβ is produced from amyloid precursor protein (APP) that is sequentially cleaved by β- and γ-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 Aβ production, we performed a gene microarray–based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because Aβ 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 Aβ production. GPLD1 overexpression in HEK293 cells increased the secretion of galectin 3–binding protein (GAL3BP), which suppressed Aβ production in an AD model, neuroglioma H4 cells. Mechanistically, GAL3BP suppressed Aβ production by directly interacting with APP and thereby inhibiting APP processing by β-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.
Highlights
We previously reported that neuronal cells that are differentiated from human Induced pluripotent stem (iPS) cells express amyloid precursor protein (APP) and secrete A into the culture medium [19]
We paid attention to GPLD1 encoding glycophosphatidylinositol-specific phospholipase D1, which cleaves the inositol phosphate linkage in proteins modified with a GPI anchor [21, 22], because A is produced from APP in lipid rafts where GPI-anchored proteins are associated [23, 24]
We found that galectin 3– binding protein (GAL3BP) directly suppresses the -cut of APP and reduces A production
Summary
We previously reported that neuronal cells that are differentiated from human iPS (hiPS) cells express APP and secrete A into the culture medium [19]. The addition of the commercially available GAL3BP to the H4-APPsw culture media did not affect the processing of NRG1, another substrate of BACE1, whereas the addition of BACE1 inhibitor, which directly binds to the active site of BACE1, increased the amount of full-length NRG1 (Fig. 6, g and h). These data may suggest a selective suppression of APP processing by GAL3BP through direct interaction. Our data demonstrate that GAL3BP suppresses the pathogenic production of A via modulating the -cut of APP
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