Haas C, Hung A Y, Citron M, Teplow D B, Selkoe D J
Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Arzneimittelforschung. 1995 Mar;45(3A):398-402.
Alzheimer's disease (AD) is a neurodegenerative disorder resulting in the deposition of amyloid beta-peptide (A beta) in senile plaques in cerebral and limbic corteces and the walls of meningeal and cerebral blood vessels. A beta is a proteolytic break-down product of a membrane bound precursor, the beta-amyloid precursor protein (beta APP). Conventional secretory processing of beta APP prevents A beta formation. An additional processing pathway of beta APP involving endosomal/lysosomal targeting is described. Within isolated lysosomes amygloidogenic fragments are found which might serve as precursors for A beta production. From such precursors A beta might be proteolytically processed. Indeed, secreted A beta was identified in the media of cultured cells. A beta is also secreted in vivo and can be detected in human plasma and cerebral spinal fluid. These findings provide a cellular system to analyze the molecular mechanism and the biological regulation of A beta generation. Furthermore, the effect of inherited mutations within the beta APP gene in some cases of familial AD can now be analyzed in such tissue culture cells transfected with the mutant cDNA constructs. A model will be presented proposing that A beta generation might occur during reinternalization of the full-length molecule.
阿尔茨海默病（AD）是一种神经退行性疾病，会导致淀粉样β肽（Aβ）沉积于大脑和边缘皮质的老年斑以及脑膜和脑血管壁中。Aβ是膜结合前体β淀粉样前体蛋白（βAPP）的蛋白水解降解产物。βAPP的常规分泌加工可防止Aβ形成。本文描述了βAPP涉及内体/溶酶体靶向的另一种加工途径。在分离的溶酶体中发现了淀粉样生成片段，它们可能是Aβ产生的前体。Aβ可能从这些前体经蛋白水解加工而来。实际上，在培养细胞的培养基中已鉴定出分泌的Aβ。Aβ也在体内分泌，并且可以在人血浆和脑脊液中检测到。这些发现提供了一个细胞系统来分析Aβ生成的分子机制和生物学调节。此外，现在可以在转染了突变cDNA构建体的此类组织培养细胞中分析βAPP基因内的遗传突变在某些家族性AD病例中的作用。将提出一个模型，认为Aβ生成可能发生在全长分子再内化过程中。
