Cerebrovascular Accumulation and Increased Blood-Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy


Address correspondence and reprint requests to Dr. B. V. Zlokovic at Department of Neurological Surgery and Division of Neurosurgery, Children's Hospital, 2025 Zonal Avenue, RMR 506, Los Angeles, CA 90033, U.S.A.


Abstract: Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestration and blood-brain barrier (BBB) permeability to 125I-amyloid β(1-40) synthetic peptide (sAβ1-40) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half-time of elimination of sAβ1-40, te1/2, was prolonged by 0.6 h, the systemic clearance, ClSS, was reduced from 1.8 to 1.1 ml/min/kg, and the mean residence time of intact peptide in the circulation was increased by 1 h (45%). In adult monkey, cerebrovascular sequestration of intact sAβ1-40 was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sAβ1-40 by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8-, and 2.1-fold, respectively, in the presence of an unchanged barrier to inulin. In brain parenchyma of aged animals, 76.1% of circulating sAβ1-40 remained intact versus 45.7% in adult. We conclude that multiple age-related systemic effects, i.e., reduced body elimination and systemic clearance of sAβ1-40, and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sAβ1-40, and reduced brain metabolism to enhance the development of CAA.