Cerebrovascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer's 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 sequestration and blood-brain barrier (BBB) permeability to 121I-amyloid beta(1-40) synthetic peptide (sA beta(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 sA beta(1-40), t(1/2)e, 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 sA beta(1-40) was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sA beta(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 sA beta(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 sA beta(1-40), and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sA beta(1-40), and reduced brain metabolism to enhance the development of CAA.
Mackic
J B
JB
Department of Neurological Surgery, Children's Hospital, Los Angeles, California 90033, USA.
Weiss
M H
MH
Miao
W
W
Kirkman
E
E
Ghiso
J
J
Calero
M
M
Bading
J
J
Frangione
B
B
Zlokovic
B V
BV
D000375:Aging / Q000097:blood*; D000544:Alzheimer Disease / Q000097:blood; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology*; D016657:Cerebral Amyloid Angiopathy / Q000097:blood*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D011232:Chemical Precipitation; D010446:Peptide Fragments / Q000097:blood / Q000493:pharmacokinetics; D012453:Saimiri; D014018:Tissue Distribution; D014238:Trichloroacetic Acid
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D014238:Trichloroacetic Acid