Narita M, Holtzman D M, Schwartz A L, Bu G
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, U.S.A.
J Neurochem. 1997 Nov;69(5):1904-11. doi: 10.1046/j.1471-4159.1997.69051904.x.
A primary histopathological feature of Alzheimer's disease is the accumulation of beta-amyloid (A beta) in the brain of afflicted individuals. However, A beta is produced continuously as a soluble protein in healthy individuals where it is detected in serum and CSF, suggesting the existence of cellular clearance mechanisms that normally prevent its accumulation and aggregation. Here, we demonstrate that A beta forms stable complexes with activated alpha2-macroglobulin (alpha2M*), a physiological ligand for the low-density lipoprotein receptor-related protein (LRP) that is abundantly expressed in the CNS. These alpha2M*/125I-A beta complexes are immunoreactive with both anti-A beta and anti-alpha2M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that alpha2M*/125I-A beta complexes can be degraded by glioblastoma cells and fibroblasts via LRP, because degradation is partially inhibited by receptor-associated protein (RAP), an antagonist of ligand interactions with LRP. In contrast, the degradation of free 125I-A beta is not inhibited by RAP and thus must be mediated via an LRP-independent pathway. These results suggest that LRP can function as a clearance receptor for A beta via a physiological ligand.
阿尔茨海默病的一个主要组织病理学特征是β-淀粉样蛋白（Aβ）在患病个体大脑中的积累。然而，在健康个体中，Aβ作为一种可溶性蛋白持续产生，并在血清和脑脊液中被检测到，这表明存在正常情况下可防止其积累和聚集的细胞清除机制。在此，我们证明Aβ与活化的α2-巨球蛋白（α2M*）形成稳定复合物，α2M是低密度脂蛋白受体相关蛋白（LRP）的一种生理配体，在中枢神经系统中大量表达。这些α2M/125I-Aβ复合物与抗Aβ和抗α2M IgG均具有免疫反应性，并且在各种pH条件、十二烷基硫酸钠、还原剂和煮沸情况下均稳定。我们证明α2M*/125I-Aβ复合物可被胶质母细胞瘤细胞和成纤维细胞通过LRP降解，因为降解被受体相关蛋白（RAP）部分抑制，RAP是配体与LRP相互作用的拮抗剂。相比之下，游离125I-Aβ的降解不受RAP抑制，因此必定通过不依赖LRP的途径介导。这些结果表明LRP可通过一种生理配体作为Aβ的清除受体发挥作用。
