Kranenburg O, Gent Y Y J, Romijn E P, Voest E E, Heck A J R, Gebbink M F B G
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Neuroscience. 2005;131(4):877-86. doi: 10.1016/j.neuroscience.2004.11.044.
Alzheimer's disease brain is characterized by the abundant presence of amyloid deposits. Accumulation of the major constituent of these deposits, amyloid-beta (Abeta), has been associated with decreased neurotransmission, increased neuronal cell death, and with cognitive decline. The mechanisms underlying these phenomena have not yet been fully elucidated. We have previously shown that amyloid peptides like Abeta bind tissue-type plasminogen activator (tPA) and cause enhanced plasmin production. Here we describe the identification of five major neuronal cell-produced Abeta-associated proteins and how Abeta-stimulated plasmin formation affects their processing. These five proteins are all neuroendocrine factors (NEFs): chromogranins A, B and C; truncated chromogranin B; and VGF. Plasminogen caused processing of Abeta-bound (but not soluble) tPA, chromogranin B and VGF and the degradation products were released from Abeta. Processing of the neuroendocrine factors was dependent on tPA as it was largely abrogated in tPA-/- cells or in the presence of a specific tPA-inhibitor. If plasmin indeed produces NEF-derived peptides in vivo, some of these peptides may have biological activity, for instance in regulating neurotransmitter release that may affect the pathology of Alzheimer's disease.
阿尔茨海默病大脑的特征是存在大量淀粉样沉积物。这些沉积物的主要成分β淀粉样蛋白（Aβ）的积累与神经传递减少、神经元细胞死亡增加以及认知能力下降有关。这些现象背后的机制尚未完全阐明。我们之前已经表明，像Aβ这样的淀粉样肽会结合组织型纤溶酶原激活物（tPA）并导致纤溶酶产生增加。在此，我们描述了五种主要的神经元细胞产生的与Aβ相关的蛋白的鉴定，以及Aβ刺激的纤溶酶形成如何影响它们的加工过程。这五种蛋白均为神经内分泌因子（NEFs）：嗜铬粒蛋白A、B和C；截短的嗜铬粒蛋白B；以及VGF。纤溶酶原导致与Aβ结合的（而非可溶性的）tPA、嗜铬粒蛋白B和VGF的加工，并且降解产物从Aβ中释放出来。神经内分泌因子的加工依赖于tPA，因为在tPA基因敲除细胞中或存在特异性tPA抑制剂时，这种加工过程在很大程度上被消除。如果纤溶酶确实在体内产生源自NEF的肽，那么其中一些肽可能具有生物活性，例如在调节神经递质释放方面，这可能会影响阿尔茨海默病的病理过程。
