Zlokovic B V
Department of Neurological Surgery, Childrens Hospital Los Angeles, USC School of Medicine 90033, USA.
Life Sci. 1996;59(18):1483-97. doi: 10.1016/0024-3205(96)00310-4.
It is uncertain whether soluble circulating amyloid beta (sA beta) is the precursor of amyloid beta (A beta) found in cerebrovascular and parenchymal amyloid lesions in Alzheimer's Disease, and if so, how the transition to the filamentous form is brought about. Several lines of evidence suggest that apolipoprotein E (apoE) and apolipoprotein J (apoJ) may be involved in the regulation of amyloidogenesis. They both bind sA beta/A beta in vivo and in vitro. It has been suggested that apoE may modulate beta-pleated conformation of A beta and therefore act as a proamyloidogenic factor. On the other hand, apoJ as a major carrier protein of sA beta in body fluids may keep the peptide in a soluble form, thus having an anti-amyloidogenic effect. Using a well established guinea-pig brain perfusion model we have studied the blood-brain barrier (BBB) processes involved in the regulation of cerebral capillary sequestration, transport and metabolism of i) sA beta 1-40 and sA beta 1-42, synthetic peptides identical to the 40 and 42 residue forms of A beta, found primarily in vascular deposits and senile plaques, respectively; and ii) apoJ, apoE3 and apoE4 alone, and in a complex with sA beta. Specific saturable BBB luminal binding of both peptides was followed by transport into brain parenchyma and metabolism at the abluminal side of the BBB and/or in brain. The capillary sequestration of sA beta 1-40 was significant, while retention by the microvasculature of sA beta 1-42 was negligible. Binding to microvessels and blood-to-brain transport of both intact apoJ and sA beta 1-40 apoJ complexes were among the highest ever recorded for peptides and proteins at the BBB in vivo. These processes appear to be mediated by glycoprotein 330 (gp330/megalin), a receptor for multiple ligands, including apoJ. In contrast, capillary retention and transport of apoE3, apoE4 and sA beta 1-40-apoE3 complex were low to negligible, while blood-brain transport of sA beta 1-40-apoE4 was moderate. It is suggested that normal BBB may have predominantly anti-amyloidogenic functions by i) degrading sA beta during blood-to-brain transport; ii) favoring sequestration and transport of apoJ alone and in complex with sA beta via gp330 receptor-mediated mechanism and iii) excluding apoE3 and apoE4 isoforms from brain.
可溶性循环淀粉样β蛋白（sAβ）是否是在阿尔茨海默病脑血管和实质淀粉样病变中发现的淀粉样β蛋白（Aβ）的前体尚不确定，若如此，向丝状形式的转变是如何发生的也不清楚。有几条证据表明载脂蛋白E（apoE）和载脂蛋白J（apoJ）可能参与淀粉样蛋白生成的调节。它们在体内和体外均能结合sAβ/Aβ。有人提出apoE可能调节Aβ的β折叠构象，因此作为一种促淀粉样蛋白生成因子起作用。另一方面，apoJ作为体液中sAβ的主要载体蛋白，可能使该肽保持可溶形式，从而具有抗淀粉样蛋白生成作用。利用一个成熟的豚鼠脑灌注模型，我们研究了血脑屏障（BBB）过程，这些过程参与调节脑毛细血管对以下物质的隔离、运输和代谢：i）sAβ1-40和sAβ1-42，这两种合成肽分别与主要在血管沉积物和老年斑中发现的Aβ的40和42个残基形式相同；ii）单独的apoJ、apoE3和apoE4，以及与sAβ形成的复合物。两种肽在BBB腔面的特异性可饱和结合之后是向脑实质的转运以及在BBB腔外侧面和/或脑中的代谢。sAβ1-40的毛细血管隔离显著，而sAβ1-42被微血管保留的量可忽略不计。完整的apoJ和sAβ1-40-apoJ复合物与微血管的结合以及血脑转运是体内BBB处肽和蛋白质所记录到的最高值之一。这些过程似乎由糖蛋白330（gp330/巨膜蛋白）介导，它是包括apoJ在内的多种配体的受体。相比之下，apoE3、apoE4和sAβ1-40-apoE3复合物的毛细血管保留和转运很低或可忽略不计，而sAβ1-40-apoE4的血脑转运适中。有人提出正常的BBB可能主要具有抗淀粉样蛋白生成功能，方式如下：i）在血脑转运过程中降解sAβ；ii）通过gp330受体介导的机制促进单独的apoJ以及与sAβ形成的复合物的隔离和转运；iii）将apoE3和apoE4异构体排除在脑外。
