Synaptic Vesicle Glycoprotein 2A Slows down Amyloidogenic Processing of Amyloid Precursor Protein <i>via</i> Regulating Its Intracellular Trafficking.

Qian ZHANG; Xiao Ling WANG; Yu Li HOU; Jing Jing ZHANG; Cong Cong LIU; Xiao Min ZHANG; Ya Qi WANG; Yu Jian FAN; Jun Ting LIU; Jing LIU; Qiao SONG; Pei Chang WANG

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Synaptic Vesicle Glycoprotein 2A Slows down Amyloidogenic Processing of Amyloid Precursor Protein via Regulating Its Intracellular Trafficking.

Author: Qian ZHANG ¹ ; Xiao Ling WANG ² ; Yu Li HOU ¹ ; Jing Jing ZHANG ¹ ; Cong Cong LIU ¹ ; Xiao Min ZHANG ¹ ; Ya Qi WANG ¹ ; Yu Jian FAN ¹ ; Jun Ting LIU ¹ ; Jing LIU ¹ ; Qiao SONG ¹ ; Pei Chang WANG ¹
Author Information

1. Department of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical University, Beijing 100053, China.
2. Department of Clinical Laboratory, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical University, Beijing 100053, China;Department of Clinical Laboratory, Changzhi People's Hospital of Changzhi Medical College, Changzhi 046000, Shanxi, China.
Publication Type:Journal Article
Keywords: Alzheimer’s disease; Amyloid degradation; Amyloid precursor protein; Endolysosomal system; Synaptic vesicle glycoprotein 2A
MeSH: Amyloid beta-Protein Precursor/genetics*; Membrane Glycoproteins/genetics*; Animals; Protein Transport; Nerve Tissue Proteins/genetics*; Humans; Mice; Endosomes/metabolism*; trans-Golgi Network/metabolism*
From: Biomedical and Environmental Sciences 2025;38(5):607-624
CountryChina
Language:English
Abstract: 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, Aβ _1-42, and Aβ _1-40, 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.