Banks W A, Robinson S M, Verma S, Morley J E
Geriatrics Research Educational and Clinical Center, Veterans Affairs Medical Center-St. Louis and Division of Geriatrics, Department of Internal Medicine, St. Louis University School of Medicine, St. Louis, MO 63106, USA.
Neuroscience. 2003;121(2):487-92. doi: 10.1016/s0306-4522(03)00474-3.
Brain to blood transport is believed to be a major determinant of the amount of amyloid beta protein (AbetaP) found in brain. Impaired efflux has been suggested as a mechanism by which AbetaP 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 AbetaP most relevant to AD, AbetaP1-42, has been conducted, even though a single amino acid substitution in AbetaP can greatly alter efflux. Here, we examined the efflux of AbetaP mouse1-42, mouse1-40, human1-42, and human1-40 in young CD-1, young senesence accelerated mouse (SAM) P8, and aged SAMP8 mice. The SAMP8 mouse with aging spontaneously overproduces AbetaP and develops cognitive impairments reversed by AbetaP-directed antibody or phosphorothioate antisense oligonucleotide. CD-1 mice transported all forms of AbetaP, although mouse1-42 and human1-40 were transported 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 AbetaP among the three groups of mice supports the hypothesis that impaired efflux is an important factor in the accumulation of AbetaP in the CNS.
脑向血液的转运被认为是脑中淀粉样β蛋白（AβP）含量的主要决定因素。有研究表明，外排功能受损是AβP在中枢神经系统（CNS）中积累并导致阿尔茨海默病（AD）的一种机制。然而，迄今为止，尚未对与AD最相关的AβP形式即AβP1 - 42的外排进行研究，尽管AβP中的单个氨基酸替换会极大地改变外排。在此，我们检测了年轻CD - 1小鼠、年轻快速老化小鼠（SAM）P8以及老年SAMP8小鼠中AβP小鼠1 - 42、小鼠1 - 40、人1 - 42和人1 - 40的外排情况。随着年龄增长，SAMP8小鼠会自发过度产生AβP并出现认知障碍，而针对AβP的抗体或硫代磷酸酯反义寡核苷酸可逆转这种障碍。CD - 1小鼠能转运所有形式的AβP，不过小鼠1 - 42和人1 - 40的转运速度比其他形式更快。无论年龄大小，SAMP8小鼠中小鼠1 - 42的可饱和转运均有所下降。在年轻的SAMP8小鼠中，小鼠1 - 40和人1 - 42的外排仅通过非饱和机制进行，而在老年SAMP8小鼠中则完全不存在外排。三组小鼠中不同形式AβP外排的这些差异支持了以下假说：外排功能受损是AβP在CNS中积累的一个重要因素。
