Brain Clearance of Alzheimer's Amyloid-β40 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- β 40 peptide (A β 40) 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 123 I-A β 40 and 99m Tc-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 123 I-A β 40 with an initial rapid washout (1.1 ≤ t 1/2 ≤ 2.7 h). This, plus the observed appearance of 123 I-radioactivity in plasma suggest significant brain-to-blood transport. In contrast, 99m Tc-DTPA was removed slowly by brain interstitial fluid bulk flow (monoexponential decay with 6.8 ≤ t 1/2 ≤ 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 123 I-A β from the brain. This correlated with an age-dependent increase in A β 40/42 cerebrovascular immunoreactivity and amyloid deposition. Thus, vascular clearance plays an important role in reducing A β levels in the squirrel monkey brain and impaired A β 40 elimination across the BBB may contribute to the development of CAA.