RRC ID 76705
Author Tachida Y, Iijima J, Takahashi K, Suzuki H, Kizuka Y, Yamaguchi Y, Tanaka K, Nakano M, Takakura D, Kawasaki N, Saito Y, Manya H, Endo T, Kitazume S.
Title O-GalNAc glycosylation determines intracellular trafficking of APP and Aβ production.
Journal J Biol Chem
Abstract A primary pathology of Alzheimer's disease (AD) is amyloid β (Aβ) deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy (CAA). Parenchymal amyloid plaques presumably originate from neuronal Aβ precursor protein (APP). Although vascular amyloid deposits' origins remain unclear, endothelial APP expression in APP knock-in mice was recently shown to expand CAA pathology, highlighting endothelial APP's importance. Furthermore, two types of endothelial APP-highly O-glycosylated APP and hypo-O-glycosylated APP-have been biochemically identified, but only the former is cleaved for Aβ production, indicating the critical relationship between APP O-glycosylation and processing. Here, we analyzed APP glycosylation and its intracellular trafficking in neurons and endothelial cells. Although protein glycosylation is generally believed to precede cell surface trafficking, which was true for neuronal APP, we unexpectedly observed that hypo-O-glycosylated APP is externalized to the endothelial cell surface and transported back to the Golgi apparatus, where it then acquires additional O-glycans. Knockdown of genes encoding enzymes initiating APP O-glycosylation significantly reduced Aβ production, suggesting this non-classical glycosylation pathway contributes to CAA pathology and is a novel therapeutic target.
Volume 299(7)
Pages 104905
Published 2023-7-1
DOI 10.1016/j.jbc.2023.104905
PII S0021-9258(23)01933-6
PMID 37302553
PMC PMC10344954
MeSH Acetylgalactosamine* / metabolism Alzheimer Disease* / complications Alzheimer Disease* / metabolism Alzheimer Disease* / pathology Amyloid beta-Peptides* / biosynthesis Amyloid beta-Peptides* / chemistry Amyloid beta-Peptides* / metabolism Amyloid beta-Protein Precursor* / chemistry Amyloid beta-Protein Precursor* / metabolism Animals Cerebral Amyloid Angiopathy* / complications Cerebral Amyloid Angiopathy* / metabolism Cerebral Amyloid Angiopathy* / pathology Endothelial Cells / metabolism Glycosylation* Golgi Apparatus / metabolism Mice Neurons / metabolism Protein Transport
IF 4.238
DNA material pCALNL5 (RDB01862)