CEREBROVASCULAR ACCUMULATION AND INCREASED BLOOD-BRAIN-BARRIER PERMEABILITY TO CIRCULATING ALZHEIMERS AMYLOID-BETA PEPTIDE IN AGED SQUIRREL-MONKEY WITH CEREBRAL AMYLOID ANGIOPATHY

Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestrati on and blood-brain barrier (BBB) permeability to I-125-amyloid beta(1- 40) synthetic peptide (sA beta(1-40)) were studied in adult versus age d squirrel monkey 1 h after a single intravenous injection. In aged mo nkey, the half-time of elimination of sA beta(1-40),t(1/2)(e), was pro longed by 0.6 h, the systemic clearance, C/(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, cerebrovascu lar sequestration of intact sA beta(1-40) was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, th e sequestration of intact sA beta(1-40) by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8-, an d 2.1-fold, respectively, in the presence of an unchanged barrier to i nulin. In brain parenchyma of aged animals, 76.1% of circulating SA be ta(1-40) remained intact versus 45.7% in adult. We conclude that multi ple age-related systemic effects, i.e., reduced body elimination and s ystemic clearance of sA beta(1-40) and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendotheli al transport and microvascular accumulation of blood-borne sA beta(1-4 0), and reduced brain metabolism to enhance the development of CAA.