Clear Search sequence regions


Sizes of these terms reflect their relevance to your search.

Alzheimer's disease is associated with increased levels of amyloid beta (Aβ) generated by sequential intracellular cleavage of amyloid precursor protein (APP) by membrane-bound secretases. However, the spatial and temporal APP cleavage events along the trafficking pathways are poorly defined. Here, we use the Retention Using Selective Hooks (RUSH) to compare in real time the anterograde trafficking and temporal cleavage events of wild-type APP (APPwt) with the pathogenic Swedish APP (APPswe) and the disease-protective Icelandic APP (APPice). The analyses revealed differences in the trafficking profiles and processing between APPwt and the APP familial mutations. While APPwt was predominantly processed by the β-secretase, BACE1, following Golgi transport to the early endosomes, the transit of APPswe through the Golgi was prolonged and associated with enhanced amyloidogenic APP processing and secretion. A 20°C block in cargo exit from the Golgi confirmed β- and γ-secretase processing of APPswe in the Golgi. Inhibition of the β-secretase, BACE1, restored APPswe anterograde trafficking profile to that of APPwt. APPice was transported rapidly through the Golgi to the early endosomes with low levels of production. This study has revealed different intracellular locations for the preferential cleavage of APPwt and APPswe and production, and the Golgi as the major processing site for APPswe, findings relevant to understand the molecular basis of Alzheimer's disease. © 2024 The Authors. Traffic published by John Wiley & Sons Ltd.

Citation

Jingqi Wang, Paul A Gleeson, Lou Fourriere. Spatial-Temporal Mapping Reveals the Golgi as the Major Processing Site for the Pathogenic Swedish APP Mutation: Familial APP Mutant Shifts the Major APP Processing Site. Traffic (Copenhagen, Denmark). 2024 Mar;25(3):e12932

Expand section icon Mesh Tags

Expand section icon Substances


PMID: 38528836

View Full Text