title: Traffic jam at the blood-brain barrier promotes greater accumulation of Alzheimer's disease amyloid-β proteins in the cerebral vasculature.
abstract: Amyloid-β (Aβ) deposition in the brain vasculature results in cerebral amyloid angiopathy (CAA), which occurs in about 80% of Alzheimer's disease (AD) patients. While Aβ42 predominates parenchymal amyloid plaques in AD brain, Aβ40 is prevalent in the cerebrovascular amyloid. Dutch mutation of Aβ40 (E22Q) promotes aggressive cerebrovascular accumulation and leads to severe CAA in the mutation carriers; knowledge of how DutchAβ40 drives this process more efficiently than Aβ40 could reveal various pathophysiological events that promote CAA. In this study we have demonstrated that DutchAβ40 shows preferential accumulation in the blood-brain-barrier (BBB) endothelial cells due to its inefficient blood-to-brain transcytosis. Consequently, DutchAβ40 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 Aβ40 is not robust enough to exercise such a significant impact on its brain clearance. Hence, the cerebrovascular accumulation of Aβ40 is slow and may require other copathologies to precipitate into CAA. In conclusion, the magnitude of Aβ accumulation in the BBB endothelial cells is a critical factor that promotes CAA; hence, clearing vascular endothelium of Aβ proteins may halt or even reverse CAA.
authors.affiliation: Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, United States.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Agyare
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Leonard
authors.forename: Geoffry L
authors.initials: GL
authors.lastname: Curran
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Yu
authors.forename: Val J
authors.initials: VJ
authors.lastname: Lowe
authors.forename: Anant K
authors.initials: AK
authors.lastname: Paravastu
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Poduslo
authors.forename: Karunya K
authors.initials: KK
authors.lastname: Kandimalla
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008959:Models, Neurological; D050505:Mutant Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D057900:Transcytosis
chemical_list: D016229:Amyloid beta-Peptides; D050505:Mutant Proteins