在一项新的研究中,来自英国伦敦国王学院的Diane Hanger和她的同事们发现在没有细胞死亡的情况下,神经元活性能够刺激健康的神经元释放tau蛋白.这一研究结果证实利用已知的生物信号分子处理神经元能够增加tau蛋白释放到培养基中.相关研究结果于2013年2月15日在线发表在EMBO reports期刊上,论文标题为"Physiological release of endogenous tau is stimulated by neuronal activity".
因此,皮质神经元(cortical neuron)释放tau蛋白是一种能够受到神经元活性调节的生理学过程.
tau蛋白能够让微管保持稳定,其中微管是由聚合物连接在一起而形成的长长的管状结构,它有助于维持细胞的结构.然而,在阿尔茨海默病(Alzheimer's disease)或某些类型的痴呆症中,tau蛋白在神经元或神经胶质细胞中堆积在一起,从而导致神经退化.
除了在细胞内堆积外,最近的实验已证实tau蛋白是由神经元释放,并被附近的细胞摄取,从而允许堆积的tau蛋白在整个大脑组织中扩散.尽管一些证据已提示着tau蛋白释放可能在神经元死亡和神经退化之前就已发生,但是这也可能是由即将死亡的神经元被动发生的.这项新的研究表明tau蛋白释放是一种在健康神经元中主动发生的过程,但在患病的大脑中,这可能发生改变.
论文共同作者Diane Hanger评论道,"我们的发现提示着在阿尔茨海默病患者的大脑中,发生改变的tau蛋白释放可能是对神经元激发性能变化作出的反应而产生的.因此,分泌的tau蛋白可能参与tau蛋白病(taupathy)中的tau病理特征扩增,其中tau蛋白病是一组与tau蛋白在大脑中堆积相关联的疾病."在这些实验中,论文第一作者Amy Pooler揭示出诸如氯化钾、谷氨酸或AM-PA受体拮抗剂之类的分子能够让皮质神经元释放tau蛋白,其中这种释放是一种主动的生理过程,而且至少部分上依赖于突触前的囊泡分泌(vesicle secretion).
这些新的发现表明除了tau蛋白让微管保持稳定外,它也在细胞之间的生物信号转导过程中发挥着之前未知的作用.
Hanger说,"我们认为靶向tau蛋白释放过程可能是一种新的治疗方法来医治阿尔茨海默病和相关的tau蛋白病."不过科学家们还需要在模式生物中开展研究来进一步测试这种推测.(生物谷Bioon.com)
doi:10.1038/embor.2013.15
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Physiological release of endogenous tau is stimulated by neuronal activity
Amy M Pooler1, Emma C Phillips1, Dawn H W Lau1, Wendy Noble1 & Diane P Hanger1
In Alzheimer’s disease and related disorders, characteristic neuropathological depositions of the cytoskeletal protein tau spread progressively from the entorhinal cortex to anatomically connected brain regions [1, 2]. Moreover, injection of brain extracts from mice expressing P301S mutant tau into brains of transgenic mice expressing wild-type tau induced tau pathology that spread from the site of injection to adjacent brain regions [3]. The mechanisms controlling neuronal transmission of tau pathology are unknown, but one possibility is that tau, the primary component of neurofibrillary tangles, is released following neuronal death, allowing it to be taken up by neighbouring cells [4]. However, in two lines of transgenic mice overexpressing a single isoform of mutant tau (P301L), known to cause fronto-temporal dementia, inter-neuronal transfer of mutant tau appears to occur before any marked neurodegeneration [5, 6]. Moreover, tau pathology appeared to cross synapses; monosynaptic spread leading to the induction of tau pathology in neighbouring entorhinal neurons, and trans-synaptic spread causing tau pathology to appear in hippocampal pyramidal neurons. This suggests that propagation of tau pathology is an active process, associated with synapses, and might not be due solely to the release of tau from dying neurons. This indicates therefore that tau release from healthy neurons could be a physiological process that might be disrupted in diseased brain.
Several recent studies suggest that tau, which is viewed primarily as a microtubule-associated protein, is released from viable cells, often in association with membrane-bound exosomes or vesicles [7–11]. However, the majority of these studies measured the tau content in culture medium from cell lines overexpressing exogenous human tau, or from non-mammalian neurons. While the physiological relevance of these observations is not certain, these findings are supported by the recent observation that endogenous tau is released from induced pluripotent stem cell-derived human neurons in the absence of marked cell death [10]. Taken together, these observations imply that tau release from cells might be a physiologically regulated process. However, the mechanism underlying neuronal tau release is not yet understood.
We have examined the mechanisms underlying endogenous tau release from mature cortical neurons in culture. We show here that tau is released from neurons in the absence of cell death and that this process is regulated by neuronal activity. We provide evidence that stimulation of AMPA, but not NMDA, receptors increases tau release through a mechanism that is dependent on calcium and exocytosis of pre-synaptic vesicles, and that secreted tau is largely non-exosomal. These data suggest that altered tau release is likely to occur in response to regional changes in neuronal excitability in the Alzheimer’s brain, and that secreted tau might underlie the propagation of tau pathology in tauopathies. Therefore, targeting tau release could be explored as a new therapeutic approach for the treatment of Alzheimer’s disease and related tauopathies.