Park So-Young, Ferreira Adriana
Department of Cell and Molecular Biology, Feinberg School of Medicine, and Institute for Neuroscience, Northwestern University, Chicago, Illinois 60611, USA.
J Neurosci. 2005 Jun 1;25(22):5365-75. doi: 10.1523/JNEUROSCI.1125-05.2005.
Recently, we have shown that the microtubule-associated protein tau is essential for beta-amyloid (Abeta)-induced neurotoxicity in hippocampal neurons. However, the mechanisms by which tau mediates Abeta-induced neurite degeneration remain poorly understood. In the present study, we analyzed whether tau cleavage played a role in these events. Our results showed that pre-aggregated Abeta induced the generation of a 17 kDa tau fragment in cultured hippocampal neurons. The generation of this fragment was preceded by the activation of calpain-1. Conversely, inhibitors of this protease, but not of caspases, completely prevented tau proteolysis leading to the generation of the 17 kDa fragment and significantly reduced Abeta-induced neuronal death. Furthermore, the expression of this fragment in cultured hippocampal neurons induced the formation of numerous varicosity-bearing tortuous processes, as well as the complete degeneration of some of those neurite processes. These results suggest that Abeta-induced neurotoxicity may be mediated, at least in part, through the calpain-mediated generation of a toxic 17 kDa tau fragment. Collectively, these results provide insight into a novel mechanism by which tau could mediate Abeta-induced neurotoxicity.
最近，我们已经表明，微管相关蛋白tau对于β-淀粉样蛋白（Aβ）诱导的海马神经元神经毒性至关重要。然而，tau介导Aβ诱导的神经突退化的机制仍知之甚少。在本研究中，我们分析了tau裂解是否在这些事件中起作用。我们的结果表明，预聚集的Aβ在培养的海马神经元中诱导产生了一个17 kDa的tau片段。该片段的产生先于钙蛋白酶-1的激活。相反，这种蛋白酶的抑制剂而非半胱天冬酶的抑制剂完全阻止了tau蛋白水解，从而导致17 kDa片段的产生，并显著减少了Aβ诱导的神经元死亡。此外，该片段在培养的海马神经元中的表达诱导了许多带有膨体的曲折突起的形成，以及其中一些神经突的完全退化。这些结果表明，Aβ诱导的神经毒性可能至少部分是通过钙蛋白酶介导产生有毒的17 kDa tau片段来介导的。总的来说，这些结果为tau介导Aβ诱导的神经毒性的新机制提供了见解。
