title: Brain clearance of Alzheimer's amyloid-beta40 in the squirrel monkey: a SPECT study in a primate model of cerebral amyloid angiopathy.
abstract: Squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Previous studies suggested that circulating amyloid-beta40 peptide (Abeta40) crosses the blood-brain barrier (BBB) and may therefore enhance cerebrovascular amyloidosis in aged squirrel monkeys. In the present study, we used single photon emission computed tomography (SPECT) to determine elimination of 123I-Abeta40 and 99mTc-DTPA, an extracellular marker, from the brain in squirrel monkeys at different age. Following intracerebral microinfusions, the time-activity brain clearance curves indicated bi-exponential removal of 123I-Abeta40 with an initial rapid washout (1.1 < or = t 1/2 < or = 2.7 h). This, plus the observed appearance of 123I-radioactivity in plasma suggest significant brain-to-blood transport. In contrast, 99mTc-DTPA was removed slowly by brain interstitial fluid bulk flow (monoexponential decay with 6.8 < or = t 1/2 < or = 16.8 h). A comparison of three middle aged (11-16 years old) vs. two old (22 yrs old) monkeys was consistent with an age-related decline in the BBB capacity to remove 123I-Abeta from the brain. This correlated with an age-dependent increase in A1beta40/42 cerebrovascular immunoreactivity and amyloid deposition. Thus, vascular clearance plays an important role in reducing Abeta levels in the squirrel monkey brain and impaired Abeta40 elimination across the BBB may contribute to the development of CAA.
authors.affiliation: Department of Radiology, USC School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Bading
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamada
authors.forename: Jasmina B
authors.initials: JB
authors.lastname: Mackic
authors.forename: Linda
authors.initials: L
authors.lastname: Kirkman
authors.forename: Carol
authors.initials: C
authors.lastname: Miller
authors.forename: Miguel
authors.initials: M
authors.lastname: Calero
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.forename: Blas
authors.initials: B
authors.lastname: Frangione
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D016657:Cerebral Amyloid Angiopathy / Q000000981:diagnostic imaging / Q000378:metabolism*; D004195:Disease Models, Animal; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D012453:Saimiri; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C419409:amyloid beta-protein (29-40)