Efflux of Human and Mouse Amyloid ß Proteins 1-40 and 1-42 From Brain: Impairment in a Mouse Model of Alzheimers Disease

摘要

Brain to blood transport is believed to be a major determinant of the amount of amyloid ß protein (AßP) found in brain. Impaired efflux has been suggested as a mechanism by which AßP can accumulate in the CNS and so lead to Alzheimer's disease (AD). To date, however, no study of the efflux of the form of AßP most relevant to AD, AßP1-42, has been conducted, even though a single amino acid substitution in AßP can greatly alter efflux. Here, we examined the efflux of AßP mouse1-42, mouse1-40, human1-42, and human1-40 in young CD-1, young SAMP8, and aged SAMP8 mice. The SAMP8 mouse with aging spontaneously overproduces AßP and develops cognitive impairments reversed by AßP-directed antibody or phosphorothioate antisense oligonucleotide. CD-1 mice transported all forms of AßP, although mouse1-42 and human1-40 were transporter faster than the other forms. There was a decrease in the saturable transport of mouse1-42 in SAMP8 mice regardless of age. Efflux of mouse1-40 and human1-42 was only by a non-saturable mechanism in young SAMP8 mice and their efflux was totally absent in aged SAMP8 mice. These differences in the efflux of the various forms of AßP among the three groups of mice supports the hypothesis that impaired efflux is an important factor in the accumulation of AßP in the CNS.