title: Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy.
abstract: Cerebral amyloid angiopathy (CAA) is caused by the cerebrovascular deposition of Alzheimer amyloid beta protein (Abeta) and shows an increased incidence in carriers of the apolipoprotein E (APOE) epsilon4 genotype. To study the pathogenesis of CAA, primary cultures of human and canine smooth muscle cells from leptomeningeal vessels were incubated with fluorescein- and biotin-conjugated amyloid beta-protein. In the presence of human serum or cerebrospinal fluid, A beta1-40 and Abeta1-42 were rapidly internalized and appeared within endosomal and lysosomal vesicles. The accumulation of intracellular Abeta was enhanced by chloroquine and blocked by cycloheximide and brefeldin A and pretreatment with trypsin, suggesting that the internalization of Abeta occurs by receptor-mediated endocytosis. The internalization of Abeta was also inhibited by lipoprotein-deficient serum or by incubation with the 39-kd receptor-associated protein, indicating that Abeta is internalized via a receptor of the low-density lipoprotein receptor family. A lipoprotein pathway was confirmed by colocalization of cell surface-bound or internalized Abeta with APOE and low-density lipoprotein receptor-related protein. We propose a pathogenetic model of CAA, in which Abeta-APOE-complexes contained within the cerebrospinal fluid or the extracellular fluid of the brain are internalized and accumulated in cerebrovascular smooth muscle cells. Such a model could explain the preferential localization of CAA to the outer and middle layers of cortical and leptomeningeal arterioles, while indicating a mechanism by which the APOE genotype might determine the risk of CAA.
authors.affiliation: Department of Neurology, University of Düsseldorf, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Urmoneit
authors.forename: I
authors.initials: I
authors.lastname: Prikulis
authors.forename: G
authors.initials: G
authors.lastname: Wihl
authors.forename: D
authors.initials: D
authors.lastname: D'Urso
authors.forename: R
authors.initials: R
authors.lastname: Frank
authors.forename: J
authors.initials: J
authors.lastname: Heeren
authors.forename: U
authors.initials: U
authors.lastname: Beisiegel
authors.forename: R
authors.initials: R
authors.lastname: Prior
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D001921:Brain / Q000098:blood supply*; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology*; D004285:Dogs; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic