Kranenburg Onno, Bouma Barend, Gent Yoony Y J, Aarsman Colinda J, Kayed Rakez, Posthuma George, Schiks Bettina, Voest Emile E, Gebbink Martijn F B G
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Mol Cell Neurosci. 2005 Mar;28(3):496-508. doi: 10.1016/j.mcn.2004.11.001.
A major component of neuritic plaques in brain tissue of Alzheimer's disease patients is the beta-amyloid peptide (Abeta). Accumulation of Abeta has been associated with increased neuronal cell death and cognitive decline. We have previously shown that amyloid peptides like Abeta bind tissue-type plasminogen activator (tPA) and stimulate plasmin production. Here we investigated how Abeta regulates plasmin formation by N1E-115 neuroblastoma cells and the effects of Abeta-mediated plasmin formation on cell attachment and cell survival. We find that Abeta induces excessive cell-associated plasmin generation that causes cell detachment. Cell detachment is inhibited by carboxypeptidase B (CPB), an enzyme that blocks plasmin formation by cleaving off C-terminal lysine residues. Plasmin and CPB control Abeta-induced cell detachment independently of direct effects on cell viability. Abeta40 as well as oligomeric and fibrillar forms of Abeta42 stimulated tPA-mediated plasminogen activation and cell detachment. Our results suggest that plasmin-mediated cell detachment could contribute to the pathological effects of Abeta in diseased brain.
阿尔茨海默病患者脑组织中神经炎性斑块的一个主要成分是β-淀粉样肽（Aβ）。Aβ的积累与神经元细胞死亡增加和认知能力下降有关。我们之前已经表明，像Aβ这样的淀粉样肽能结合组织型纤溶酶原激活剂（tPA）并刺激纤溶酶的产生。在此，我们研究了Aβ如何调节N1E-115神经母细胞瘤细胞形成纤溶酶，以及Aβ介导的纤溶酶形成对细胞黏附和细胞存活的影响。我们发现，Aβ诱导细胞相关的纤溶酶过度生成，从而导致细胞脱离。羧肽酶B（CPB）可抑制细胞脱离，CPB是一种通过切除C末端赖氨酸残基来阻止纤溶酶形成的酶。纤溶酶和CPB对Aβ诱导的细胞脱离的控制与对细胞活力的直接影响无关。Aβ40以及Aβ42的寡聚体和纤维状形式均刺激tPA介导的纤溶酶原激活和细胞脱离。我们的结果表明，纤溶酶介导的细胞脱离可能导致Aβ在患病大脑中的病理作用。
