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

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 (sAβ_1-40) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half-time of elimination of sAβ_1-40, t ^e_1/2, was prolonged by 0.6 h, the systemic clearance, Cl _SS, 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 sAβ_1-40 was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sAβ_1-40 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 sAβ_1-40 remained intact versus 45.7% in adult. We conclude that multiple age-related systemic effects, i.e., reduced body elimination and systemic clearance of sAβ_1-40, and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sAβ_1-40, and reduced brain metabolism to enhance the development of CAA.