Lack of saturable transport across the blood-brain barrier in either direction for β-amyloid 1–28 (Alzheimer's disease protein)

Abstract

β-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 β-amyloid 1–28 (βAm), a commercially available, biologically active fragment, radioactively labeled with 125I (I-βAm), to cross the BBB. After IV injection of I-βAm, 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 βAm or by pretreatment with aluminum, indicating that entry was by the nonsaturable mechanism of transmembrane diffusion. After intraventricular injection of I-βAm, radioactivity was cleared slowly from the brain and was not affected by excess unlabeled βAm or by pretreatment with aluminum, indicating mat clearance probably occurred with reabsorption of cerebrospinal fluid. The excess βAm did not alter the brain/blood ratio or the clearance rate of radioactively labeled albumin, indicating that under the conditions of this experiment βAm 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-βAm was rapidly degraded, especially by the brain, to smaller peptide fragments. These results indicate that although I-βAm or related peptides may be able to enter and exit the brain, they do so slowly by nonspecific mechanisms and are rapidly degraded. Alterations in either the degree to which βAm can cross the BBB or in its rate of degradation by either the brain or the blood could affect its ability to accumulate in the brain.