Brain Endothelial Cells Produce Amyloid β from Amyloid Precursor Protein 770 and Preferentially Secrete the O-Glycosylated Form

Deposition of amyloid beta(A beta) in the brain is closely associated with Alzheimer disease (AD). A beta is generated from amyloid precursor protein (APP) by the actions of beta- and gamma-secretases. In addition to A beta deposition in the brain parenchyma, deposition of A beta in cerebral vessel walls, termed cerebral amyloid angiopathy, is observed in more than 80% of AD individuals. The mechanism for how A beta accumulates in blood vessels remains largely unknown. In the present study, we show that brain endothelial cells expressed APP770, a differently spliced APP mRNA isoform from neuronal APP695, and produced A beta 40 and A beta 42. Furthermore, we found that the endothelial APP770 had sialylated core 1 type O-glycans. Interestingly, O-glycosylated APP770 was preferentially processed by both alpha- and beta-cleavage and secreted into the media, suggesting that O-glycosylation and APP processing involved related pathways. By immunostaining human brain sections with an anti-APP770 antibody, we found that APP770 was expressed in vascular endothelial cells. Because we were able to detect O-glycosylated sAPP770 beta in human cerebrospinal fluid, this unique soluble APP770 beta has the potential to serve as a marker for cortical dementias such as AD and vascular dementia.