Lack of saturable transport across the blood-brain barrier in either direction for beta-amyloid1-28 (Alzheimer's disease protein).
beta-Amyloid and related peptides are components of the neurofibrillary tangles found in the brains of patients with Alzheimer's disease and have been suggested to be directly involved in the pathophysiology of that condition. It is unclear whether the amyloid deposited in the brain arises from the peripheral circulation, which would require passage across the blood-brain barrier (BBB), or whether it is produced within the brain itself. We examined the ability of beta-amyloid1-28 (beta Am), a commercially available, biologically active fragment, radioactively labeled with 125I (I-beta Am), to cross the BBB. After IV injection of I-beta Am, radioactivity entered the brain slowly, but to a greater extent than could be attributed to its being trapped in the vascular space of the brain. Entry was not inhibited by an excess of unlabeled beta Am or by pretreatment with aluminum, indicating that entry was by the nonsaturable mechanism of transmembrane diffusion. After intraventricular injection of I-beta Am, radioactivity was cleared slowly from the brain and was not affected by excess unlabeled beta Am or by pretreatment with aluminum, indicating that clearance probably occurred with reabsorption of cerebrospinal fluid. The excess beta Am did not alter the brain/blood ratio or the clearance rate of radioactively labeled albumin, indicating that under the conditions of this experiment beta Am did not have measurable effects on BBB integrity or on the rate of reabsorption of cerebrospinal fluid. High performance liquid chromatography (HPLC) showed that I-beta Am was rapidly degraded, especially by the brain, to smaller peptide fragments.(ABSTRACT TRUNCATED AT 250 WORDS)
Banks
W A
WA
Endocrinology Section, VA Medical Center, University of New Orleans, LA 70146.
Kastin
A J
AJ
Barrera
C M
CM
Maness
L M
LM
D016229:Amyloid beta-Peptides / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR
D016229:Amyloid beta-Peptides