title: Circulating amyloid-beta peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer's disease lesions.
abstract: 1. We studied cerebrovascular sequestration and blood-brain barrier (BBB) permeability to [125I]- or [123I]-labeled amyloid-beta peptides (A beta) in aged rhesus and aged squirrel monkey, the nonhuman primate models of cerebral beta-amyloidosis and cerebrovascular amyloid angiopathy (CAA), respectively. 2. In aged rhesus, the half-time of elimination of [125I]A beta 1-40, t1/2e, was faster by 1.34 h, the systemic clearance, Clss, increased by 4.21 ml/min/kg and the mean residence time of intact peptide in the circulation shortened by 2 h. 3. Cerebrovascular sequestration of [125I]A beta 1-40 was significant in aged squirrel monkey (20.8 ml/g x 10(2)), but undetectable in the rhesus. 4. The permeability surface area product, PS, for [14C]inulin was low in both species (0.11-0.18 ml/g/s x 10(6)) indicating an intact barrier. 5. The BBB permeability to A beta 1-40 was 34.8- and 13.7-fold higher than for [14C]inulin in aged squirrel and rhesus, respectively, suggesting a specialized A beta transport across the BBB. 6. The single photon computed emission tomography studies confirmed a saturable [123I]A beta 1-40 transport at the BBB in primates (Km = 40 nM). 7. Brain autoradiographic analysis of [125I]A beta 1-42 or [125I]A beta 1-40 after intracarotid infusions of radiotracers confirmed co-localization of the signal with A beta-immunoreactive plaques in rhesus monkeys. 8. Metabolism of [125I]A beta 1-40 in brain and plasma was slower in aged squirrel compared to aged rhesus, by 2.9- and 2.6-fold, respectively. 9. Thus, transport of circulating A beta across the BBB contributes to brain parenchymal accumulation of amyloid in aged nonhuman primates. Negligible capillary binding, rapid systemic and brain degradation, and accelerated body elimination of blood-borne A beta, may prevent the development of CAA in rhesus in contrast to squirrel monkeys.
authors.affiliation: Department of Neurological Surgery, USC School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Jasmina B
authors.initials: JB
authors.lastname: Mackic
authors.forename: James
authors.initials: J
authors.lastname: Bading
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.forename: Larry
authors.initials: L
authors.lastname: Walker
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.forename: Blas
authors.initials: B
authors.lastname: Frangione
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000293:Adolescent; D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000097:blood* / Q000209:etiology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000493:pharmacokinetics; D000686:Amyloidosis / Q000097:blood* / Q000150:complications / Q000473:pathology; D000818:Animals; D001812:Blood-Brain Barrier; D016657:Cerebral Amyloid Angiopathy / Q000097:blood / Q000150:complications / Q000473:pathology; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008833:Microcirculation; D010446:Peptide Fragments / Q000097:blood* / Q000493:pharmacokinetics; D012453:Saimiri; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)