title: Targeting vascular amyloid in arterioles of Alzheimer disease transgenic mice with amyloid β protein antibody-coated nanoparticles.
abstract: The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that uses a monoclonal antibody against fibrillar human amyloid-β42 that is surface coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) after infusion into the external carotid artery using 3 different approaches. The first 2 approaches use a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloid deposits using confocal laser scanning microscopy. The third approach used high-field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles after infusion into the external carotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA.
authors.affiliation: Department of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. poduslo.joseph@mayo.edu
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Poduslo
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Hultman
authors.forename: Geoffry L
authors.initials: GL
authors.lastname: Curran
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Preboske
authors.forename: Ryan
authors.initials: R
authors.lastname: Chamberlain
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Marjańska
authors.forename: Michael
authors.initials: M
authors.lastname: Garwood
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wengenack
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001160:Arterioles / Q000473:pathology* / Q000648:ultrastructure; D052160:Benzothiazoles; D004195:Disease Models, Animal; D005290:Ferric Compounds; D006801:Humans; D007074:Immunoglobulin G; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D053758:Nanoparticles; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000473:pathology* / Q000648:ultrastructure; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013844:Thiazoles
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D005290:Ferric Compounds; D007074:Immunoglobulin G; D010446:Peptide Fragments; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C000499:ferric oxide; C009462:thioflavin T