Objective Beta-secretase 1 (BACE1) is the key enzyme for amyloid β (Aβ) production in the Alzheimer’s disease (AD) brain. The dystroglycan (DG) protein anchors astroglial endfeet onto cerebral blood vessels forming glia limitans, a supportive element in the blood-brain barrier. An untargeted proteomics study predicted that BACE1 downregulates DG expression. Here, this study investigated whether BACE1 modulates the protein levels of DG and its hypothetic mechanism.Methods Transient transfection technique was used to express target protein in HEK-293T cells and in primary mouse astrocytes. And the protein levels of targets were analyzed by Western blot. Quantitative polymerase chain reaction and co-immunoprecipitation were used to explore the potential mechanisms of BACE1-dependent regulation of DG.Results This study found that addition of BACE1 resulted in significantly lower levels of β subunit DG (β-DG) protein, both in HEK-293T cells and in primary mouse astrocytes. And in HEK-293T cells, this down-regulation of β-DG protein dependent on the enzyme activity of BACE1.Conclusion BACE1 lowers β-DG protein levels in HEK-293T cells and in mouse astrocytes.