Non-classical glycosylation determines intracellular trafficking of APP and Aβ production

Abstract

A primary pathology of Alzheimers disease (AD) is A{beta} deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy (CAA). Parenchymal amyloid plaques presumably originate from neuronal A{beta} precursor protein (APP), but vascular amyloid deposits origins remain unclear. Endothelial APP expression in APP-knock-in mice was recently shown to expand CAA pathology, highlighting endothelial APPs importance. Furthermore, two types of endothelial APP--with and without O-glycans--have been biochemically identified, but only the former is cleaved for A{beta} 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 APP lacking O-glycans is externalized to the endothelial cell surface and transported back to the Golgi apparatus, where it then acquires O-glycans. Knockdown of genes encoding enzymes initiating APP O-glycosylation significantly reduced A{beta} production, suggesting this non-classical glycosylation pathway contributes to CAA pathology and is a novel therapeutic target.