Koo E H, Sisodia S S, Archer D R, Martin L J, Weidemann A, Beyreuther K, Fischer P, Masters C L, Price D L
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2181.
Proc Natl Acad Sci U S A. 1990 Feb;87(4):1561-5. doi: 10.1073/pnas.87.4.1561.
In the brains of aged humans and cases of Alzheimer disease, deposits of amyloid in senile plaques are located in proximity to nerve processes. The principal component of this extracellular amyloid is beta/A4, a peptide derived from a larger amyloid precursor protein (APP), which is actively expressed in brain and systemic organs. Mechanisms that result in the proteolysis of APP to form beta/A4, previously termed beta-amyloid protein, and the subsequent deposition of the peptide in brain are unknown. If beta/A4 in senile plaques is derived from neuronally synthesized APP and deposited at locations remote from sites of synthesis, then APP must be transported from neuronal cell bodies to distal nerve processes in proximity to deposits of amyloid. In this study, using several immunodetection methods, we demonstrate that APP is transported axonally in neurons of the rat peripheral nervous system. Moreover, our investigations show that APP is transported by means of the fast anterograde component. These findings are consistent with the hypothesis of a neuronal origin of beta/A4, in which amyloid is deposited in the brain parenchyma of aged individuals and cases of Alzheimer disease. In this setting, we suggest that APP is synthesized in neurons and delivered to dystrophic nerve endings, where subsequent alterations of local processing of APP result in deposits of brain amyloid.
在老年人及阿尔茨海默病患者的大脑中，老年斑中的淀粉样蛋白沉积物位于神经突起附近。这种细胞外淀粉样蛋白的主要成分是β/A4，它是一种从更大的淀粉样前体蛋白（APP）衍生而来的肽，APP在脑和全身器官中均有活跃表达。导致APP蛋白水解形成β/A4（以前称为β淀粉样蛋白）以及随后该肽在脑内沉积的机制尚不清楚。如果老年斑中的β/A4源自神经元合成的APP并沉积在远离合成部位的地方，那么APP必须从神经元细胞体运输到靠近淀粉样蛋白沉积物的远端神经突起。在本研究中，我们使用多种免疫检测方法证明，APP在大鼠外周神经系统的神经元中通过轴突运输。此外，我们的研究表明，APP通过快速顺行成分进行运输。这些发现与β/A4的神经元起源假说一致，即在老年个体及阿尔茨海默病患者的脑实质中沉积淀粉样蛋白。在这种情况下，我们认为APP在神经元中合成并输送到营养不良的神经末梢，在那里APP局部加工的后续改变导致脑淀粉样蛋白沉积。
