Glypican 4 Regulates A Beta Internalization In Neural Stem Cells Partly Via Low-Density Lipoprotein Receptor-Related Protein 1

Neural stem cell (NSC) damage has been reported in patients with Alzheimer's disease. Intracellular A beta plays a vital role in NSC damage. Heparan sulfate proteoglycans are potent mediators of A beta enrichment in the brain. We hypothesized the heparan sulfate proteoglycan glypican 4 (Gpc4) regulates A beta internalization by NSCs. We evaluated Gpc4 expression in NSCs from P0-P2 generations using immunofluorescence. Adenovirus and lentivirus were used to regulate Gpc4 expression in NSCs and APP/PS1 mice, respectively. Co-immunoprecipitation was used to determine the relationship between Gpc4, A beta, and low-density lipoprotein receptor-related protein 1 (LRP1). Intracellular A beta concentrations were detected using enzyme-linked immunosorbent assay and immunofluorescence. The role of Gpc4/LRP1 on toxic/physical A beta-induced effects was evaluated using the JC-1 kit, terminal deoxynucleotidyl transferase dUPT nick end labeling, and western blotting. Gpc4 was stably expressed in NSCs, neurons, and astrocytes. Gpc4 was upregulated by A beta in NSCs and regulated A beta internalization. Gpc4 attenuation reduced A beta uptake; Gpc4 overexpression increased A beta uptake. Gpc4 regulated A beta internalization through LRP1 and contributed to A beta internalization and toxic/physical concentrations of A beta-induced mitochondrial membrane potential and cell apoptosis, partly via LRP1. Therefore, Gpc4 is a key regulator of A beta enrichment in NSCs. Inhibiting Gpc4 rescued the A beta-induced toxic effect and attenuated the nontoxic A beta enrichment into intracellular toxic concentrations. Gpc4 contributed to A beta internalization and toxic/physical concentrations of A beta-induced mitochondrial membrane potential damage and cell apoptosis, partly via LRP1. These findings suggest a potential role of Gpc4 in treating Alzheimer's disease at an early stage, by targeting NSCs.