Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system...Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system,and cell membranes and to reveal the effects of SV2A on APP amyloid degradation.Methods Colocalization analysis of APP with specific tagged proteins in the TGN,ensolysosomal system,and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP.APP,β-site amyloid precursor protein cleaving enzyme 1(BACE1)expressions,and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing.Results APP localization was reduced in the TGN,early endosomes,late endosomes,and lysosomes,whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons.Moreover,Arl5b(ADP-ribosylation factor 5b),a protein responsible for transporting APP from the TGN to early endosomes,was upregulated by SV2A.SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis.In addition,products of APP amyloid degradation,including sAPPβ,Aβ1-42,and Aβ1-40,were decreased in SV2A-overexpressed cells.Conclusion These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway,which slows APP amyloid degradation.展开更多
基金supported by grants from the State Key Program of the National Natural Science Foundation of China(grant number 82030064)Beijing Hospital Authority Youth Program(grant number QML20230812)+2 种基金Research and Development Foundation of Capital Medical University(grant number PYZ23052)National Natural Science Youth Cultivation Project of Xuanwu Hospital,Capital Medical University(grant number QNPY202317)Capital Medical University Research and Cultivation Fund(grant number PYZ23049).
文摘Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system,and cell membranes and to reveal the effects of SV2A on APP amyloid degradation.Methods Colocalization analysis of APP with specific tagged proteins in the TGN,ensolysosomal system,and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP.APP,β-site amyloid precursor protein cleaving enzyme 1(BACE1)expressions,and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing.Results APP localization was reduced in the TGN,early endosomes,late endosomes,and lysosomes,whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons.Moreover,Arl5b(ADP-ribosylation factor 5b),a protein responsible for transporting APP from the TGN to early endosomes,was upregulated by SV2A.SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis.In addition,products of APP amyloid degradation,including sAPPβ,Aβ1-42,and Aβ1-40,were decreased in SV2A-overexpressed cells.Conclusion These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway,which slows APP amyloid degradation.
