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Expression of B4GALNT1, an essential glycosyltransferase for the synthesis of complex gangliosides, suppresses BACE1 degradation and modulates APP processing

Yamaguchi, T;Yamauchi, Y;Furukawa, K;Ohmi, Y;Ohkawa, Y;Zhang, Q;Okajima, T;Furukawa, K;

Alzheimer's disease (AD) is the most prevalent form of dementia characterized by the extracellular accumulation of amyloid (A) peptides, which are produced by proteolytic cleavages of amyloid precursor protein (APP). Gangliosides are involved in AD pathophysiology including A deposition and APP processing, yet the detailed mechanisms are not fully understood. Here we examined how changes in the carbohydrate moiety of gangliosides alter APP processing in human melanoma cells, neuroectoderm-derived cells. We showed that forced expression of GD2, GM2 or GM1 (by introducing B4GALNT1 cDNA into cells not expressing this glycosyltransferase) results in increases of - and -site cleavages of APP with a prominent increase in -cleavage. We also showed that -site APP cleaving enzyme 1 (BACE1) protein is highly protected from the degradation in cells expressing these gangliosides, thereby increasing the expression of this protein. Unexpectedly, adding gangliosides exogenously altered neither BACE1 levels nor -site cleavage. The stabilisation of BACE1 protein led to the increase of this protein in lipid rafts, where BACE1 processes APP. Based on the current results, we propose a hitherto undisclosed link between ganglioside expression and AD; the expression of B4GALNT1 positively regulates the -site cleavage by mainly inhibiting the lysosomal degradation of BACE1 protein.