Rui Yanfang, Tiwari Priyanka, Xie Zuoping, Zheng James Q
Department of Biological Science and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China 100084.
J Neurosci. 2006 Oct 11;26(41):10480-7. doi: 10.1523/JNEUROSCI.3231-06.2006.
Defects in axonal transport are often associated with a wide variety of neurological diseases including Alzheimer's disease (AD). Beta-amyloid (Abeta) is a major component of neuritic plaques associated with pathological conditions of AD brains. Here, we report that a brief exposure of cultured hippocampal neurons to Abeta molecules resulted in rapid and severe impairment of mitochondrial transport without inducing apparent cell death and significant morphological changes. Such acute inhibition of mitochondrial transport was not associated with a disruption of mitochondria potential nor involved aberrant cytoskeletal changes. Abeta also did not elicit significant Ca2+ signaling to affect mitochondrial trafficking. However, stimulation of protein kinase A (PKA) by forskolin, cAMP analogs, or neuropeptides effectively alleviated the impairment. We also show that Abeta inhibited mitochondrial transport by acting through glycogen synthase kinase 3beta (GSK3beta). Given that mitochondria are crucial organelles for many cellular functions and survival, our findings thus identify an important acute action of Abeta molecules on nerve cells that could potentially contribute to various abnormalities of neuronal functions under AD conditions. Manipulation of GSK3beta and PKA activities may represent a key approach for preventing and alleviating Abeta cytotoxicity and AD pathological conditions.
轴突运输缺陷常与包括阿尔茨海默病（AD）在内的多种神经疾病相关。β-淀粉样蛋白（Aβ）是与AD脑病理状况相关的神经炎性斑块的主要成分。在此，我们报告，将培养的海马神经元短暂暴露于Aβ分子会导致线粒体运输迅速且严重受损，而不会诱导明显的细胞死亡和显著的形态变化。这种对线粒体运输的急性抑制与线粒体电位的破坏无关，也不涉及异常的细胞骨架变化。Aβ也不会引发显著的Ca2+信号来影响线粒体运输。然而，福斯可林、cAMP类似物或神经肽对蛋白激酶A（PKA）的刺激有效减轻了这种损伤。我们还表明，Aβ通过作用于糖原合酶激酶3β（GSK3β）来抑制线粒体运输。鉴于线粒体是许多细胞功能和生存的关键细胞器，我们的发现因此确定了Aβ分子对神经细胞的一种重要急性作用，这可能潜在地导致AD条件下神经元功能的各种异常。操纵GSK3β和PKA的活性可能是预防和减轻Aβ细胞毒性及AD病理状况的关键方法。
