在一項(xiàng)新的研究中,來(lái)自英國(guó)倫敦國(guó)王學(xué)院的Diane Hanger和她的同事們發(fā)現(xiàn)在沒(méi)有細(xì)胞死亡的情況下,神經(jīng)元活性能夠刺激健康的神經(jīng)元釋放tau蛋白.這一研究結(jié)果證實(shí)利用已知的生物信號(hào)分子處理神經(jīng)元能夠增加tau蛋白釋放到培養(yǎng)基中.相關(guān)研究結(jié)果于2013年2月15日在線發(fā)表在EMBO reports期刊上,論文標(biāo)題為"Physiological release of endogenous tau is stimulated by neuronal activity".

因此,皮質(zhì)神經(jīng)元(cortical neuron)釋放tau蛋白是一種能夠受到神經(jīng)元活性調(diào)節(jié)的生理學(xué)過(guò)程.

tau蛋白能夠讓微管保持穩(wěn)定,其中微管是由聚合物連接在一起而形成的長(zhǎng)長(zhǎng)的管狀結(jié)構(gòu),它有助于維持細(xì)胞的結(jié)構(gòu).然而,在阿爾茨海默病(Alzheimer's disease)或某些類型的癡呆癥中,tau蛋白在神經(jīng)元或神經(jīng)膠質(zhì)細(xì)胞中堆積在一起,從而導(dǎo)致神經(jīng)退化.

除了在細(xì)胞內(nèi)堆積外,最近的實(shí)驗(yàn)已證實(shí)tau蛋白是由神經(jīng)元釋放,并被附近的細(xì)胞攝取,從而允許堆積的tau蛋白在整個(gè)大腦組織中擴(kuò)散.盡管一些證據(jù)已提示著tau蛋白釋放可能在神經(jīng)元死亡和神經(jīng)退化之前就已發(fā)生,但是這也可能是由即將死亡的神經(jīng)元被動(dòng)發(fā)生的.這項(xiàng)新的研究表明tau蛋白釋放是一種在健康神經(jīng)元中主動(dòng)發(fā)生的過(guò)程,但在患病的大腦中,這可能發(fā)生改變.

論文共同作者Diane Hanger評(píng)論道,"我們的發(fā)現(xiàn)提示著在阿爾茨海默病患者的大腦中,發(fā)生改變的tau蛋白釋放可能是對(duì)神經(jīng)元激發(fā)性能變化作出的反應(yīng)而產(chǎn)生的.因此,分泌的tau蛋白可能參與tau蛋白病(taupathy)中的tau病理特征擴(kuò)增,其中tau蛋白病是一組與tau蛋白在大腦中堆積相關(guān)聯(lián)的疾病."在這些實(shí)驗(yàn)中,論文第一作者Amy Pooler揭示出諸如氯化鉀,、谷氨酸或AM-PA受體拮抗劑之類的分子能夠讓皮質(zhì)神經(jīng)元釋放tau蛋白,其中這種釋放是一種主動(dòng)的生理過(guò)程,而且至少部分上依賴于突觸前的囊泡分泌(vesicle secretion).

這些新的發(fā)現(xiàn)表明除了tau蛋白讓微管保持穩(wěn)定外,它也在細(xì)胞之間的生物信號(hào)轉(zhuǎn)導(dǎo)過(guò)程中發(fā)揮著之前未知的作用.

Hanger說(shuō),"我們認(rèn)為靶向tau蛋白釋放過(guò)程可能是一種新的治療方法來(lái)醫(yī)治阿爾茨海默病和相關(guān)的tau蛋白病."不過(guò)科學(xué)家們還需要在模式生物中開展研究來(lái)進(jìn)一步測(cè)試這種推測(cè).(生物谷Bioon.com)

doi:10.1038/embor.2013.15
PMC:
PMID:
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.