ABSTRACT
Amyloid-ß (Aß) deposition in the brain vasculature results in cerebral amyloid angiopathy (CAA), which occurs in about 80% of Alzheimer's disease (AD) patients. While Aß42 predominates parenchymal amyloid plaques in AD brain, Aß40 is prevalent in the cerebrovascular amyloid. Dutch mutation of Aß40 (E22Q) promotes aggressive cerebrovascular accumulation and leads to severe CAA in the mutation carriers; knowledge of how DutchAß40 drives this process more efficiently than Aß40 could reveal various pathophysiological events that promote CAA. In this study we have demonstrated that DutchAß40 shows preferential accumulation in the blood-brain-barrier (BBB) endothelial cells due to its inefficient blood-to-brain transcytosis. Consequently, DutchAß40 establishes a permeation barrier in the BBB endothelium, prevents its own clearance from the brain, and promotes the formation of amyloid deposits in the cerebral microvessels. The BBB endothelial accumulation of native Aß40 is not robust enough to exercise such a significant impact on its brain clearance. Hence, the cerebrovascular accumulation of Aß40 is slow and may require other copathologies to precipitate into CAA. In conclusion, the magnitude of Aß accumulation in the BBB endothelial cells is a critical factor that promotes CAA; hence, clearing vascular endothelium of Aß proteins may halt or even reverse CAA.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Blood-Brain Barrier/metabolism , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/genetics , Animals , Cattle , Cells, Cultured , Cerebral Amyloid Angiopathy, Familial/genetics , Cerebral Amyloid Angiopathy, Familial/metabolism , Endothelial Cells/metabolism , Humans , Models, Neurological , Mutant Proteins/blood , Mutant Proteins/genetics , Mutant Proteins/metabolism , Protein Transport , TranscytosisABSTRACT
PURPOSE: To design a smart nano-vehicle (SNV) capable of permeating the blood-brain barrier (BBB) to target cerebrovascular amyloid formed in both Alzheimer's disease (AD) and cerebrovascular amyloid angiopathy (CAA). METHODS: SNV consists of a chitosan polymeric core prepared through ionic gelation with tripolyphosphate. A polyamine modified F(ab') portion of IgG4.1, an anti-amyloid antibody, was coated as a biosensor on the SNV surface. A similar polymeric core coated with bovine serum albumin (BSA) served as a control nano-vehicle (CNV). The BBB uptake of (125)I-SNVs and (125)I-CNVs was evaluated in mice. The uptake and transcytosis of SNVs and CNVs across bovine brain microvascular endothelial cells (BBMECs) was evaluated using flow cytometry and confocal microscopy. RESULTS: Plasma clearance of (125)I-SNVs was nine times higher than that of the (125)I-CNVs. However, the uptake of (125)I-SNVs in various brain regions was about 8 to 11 times higher than that of (125)I-CNVs. The uptake of FITC-BSA loaded SNVs in BBMECs was twice the uptake of FITC-BSA loaded CNVs. Confocal micrographs demonstrated the uptake and transcytosis of Alexa Fluor 647 labeled SNVs, but not CNVs, across the BBMEC monolayer. CONCLUSIONS: SNVs are capable of carrying a payload of model protein across the BBB to target cerebral amyloid.
