title: Cerebral vascular leak in a mouse model of amyloid neuropathology.
abstract: In Alzheimer's disease (AD), there is increasing evidence of blood-brain barrier (BBB) compromise, usually observed as 'microbleeds' correlated with amyloid plaque deposition and apoE-ɛ4 status, raising the possibility of nanotherapeutic delivery. Molecular probes have been used to study neurovascular leak, but this approach does not adequately estimate vascular permeability of nanoparticles. We therefore characterized cerebrovascular leaks in live APP+ transgenic animals using a long circulating ∼100 nm nanoparticle computed tomography (CT) contrast agent probe. Active leaks fell into four categories: (1) around the dorsomedial cerebellar artery (DMCA), (2) around other major vessels, (3) nodular leaks in the cerebral cortex, and (4) diffuse leaks. Cortical leaks were uniformly more frequent in the transgenic animals than in age-matched controls. Leaks around vessels other than the DMCA were more frequent in older transgenics compared with younger ones. All other leaks were equally prevalent across genotypes independent of age. Ten days after injection, 4 to 5 μg of the dose was estimated to be present in the brain, roughly a half of which was in locations other than the leaky choroid plexus, and associated with amyloid deposition in older animals. These results suggest that amyloid deposition and age increase delivery of nanoparticle-borne reagents to the brain, in therapeutically relevant amounts.
authors: The Singleton Department of Pediatric Radiology, Texas Childrens Hospital, Houston, Texas, USA.
authors: Eric A
authors: EA
authors: Tanifum
authors: 1] The Singleton Department of Pediatric Radiology, Texas Childrens Hospital, Houston, Texas, USA [2] Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Gliwice, Poland.
authors: Zbigniew A
authors: ZA
authors: Starosolski
authors: Department of Neuroscience, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
authors: Stephanie W
authors: SW
authors: Fowler
authors: 1] Department of Neuroscience, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA [2] Departments of Neurology and Neurosurgery, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
authors: Joanna L
authors: JL
authors: Jankowsky
authors: The Singleton Department of Pediatric Radiology, Texas Childrens Hospital, Houston, Texas, USA.
authors: Ananth V
authors: AV
authors: Annapragada
mesh_terms: D000682:Amyloid / Q000032:analysis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000473:pathology*; D002536:Cerebral Arteries / Q000473:pathology*; D003287:Contrast Media; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles; D014057:Tomography, X-Ray Computed
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D003287:Contrast Media