改善認(rèn)知功能發(fā)生下降的年老人體內(nèi)的神經(jīng)元產(chǎn)生是老齡化社會(huì)所面臨的一個(gè)重要挑戰(zhàn),也是治療諸如阿爾茨海默病之類的神經(jīng)退行性疾病的一個(gè)主要難題.在一項(xiàng)新的研究中,法國和西班牙研究人員證實(shí)利用藥物阻斷TGF-β分子能夠改善小鼠模式動(dòng)物體內(nèi)新的神經(jīng)元產(chǎn)生.相關(guān)研究結(jié)果發(fā)表在2013年4月那期EMBO Molecular Medicine期刊上,論文標(biāo)題為"Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain".
這些結(jié)果激勵(lì)人們?nèi)ラ_發(fā)靶向療法以便能夠改善神經(jīng)元產(chǎn)生從而阻止老年人認(rèn)知能力下降和降低放射療法所導(dǎo)致的大腦損傷.
在成年大腦中,新的神經(jīng)元有規(guī)律地產(chǎn)生以便保證我們的所有認(rèn)知功能得到維持.這種神經(jīng)發(fā)生過程(neurogenesis)在多種情形下受到不利的影響,特別是在衰老過程中和對腦瘤進(jìn)行放射療法之后.根據(jù)之前的一些研究,對腦瘤進(jìn)行放射療法會(huì)導(dǎo)致我們體內(nèi)儲(chǔ)存的神經(jīng)元數(shù)量下降,從而導(dǎo)致認(rèn)知功能發(fā)生不可逆的下降.在衰老過程中,這種認(rèn)知功能下降同樣也會(huì)發(fā)生.
為此,研究人員一直在研究如何維持神經(jīng)元庫存.他們試圖發(fā)現(xiàn)哪些因子導(dǎo)致體內(nèi)神經(jīng)發(fā)生能力下降.他們的初步研究結(jié)果表明衰老或高劑量的放療都不能完全消滅神經(jīng)干細(xì)胞,其中這種干細(xì)胞能夠產(chǎn)生神經(jīng)元,因而是神經(jīng)發(fā)生的起源.這些存活下來的神經(jīng)干細(xì)胞位于大腦中的一個(gè)特定區(qū)域：側(cè)腦室下層(sub-ventricular zone, SVZ),但是它們似乎不能夠正常地發(fā)揮作用.
研究人員通過進(jìn)一步的實(shí)驗(yàn)發(fā)現(xiàn)在放射療法和衰老這兩種情形下,高水平的細(xì)胞因子TGF-β(轉(zhuǎn)化生長因子-β)讓這些神經(jīng)干細(xì)胞處于休眠狀態(tài),從而使得它們?nèi)菀装l(fā)生凋亡或者說程序性死亡,進(jìn)而降低新的神經(jīng)元數(shù)量.
論文通信作者M(jìn)arc-Andre Mouthon解釋道,"我們的研究結(jié)論是盡管在衰老期間和在接受高劑量放射療法之后,神經(jīng)發(fā)生能力下降,但是很多干細(xì)胞能夠存活幾個(gè)月的時(shí)間并且保持著它們的干性特征."
研究人員還證實(shí)利用藥物阻斷TGF-β能夠恢復(fù)接受放射療法的或衰老的小鼠體內(nèi)新的神經(jīng)元產(chǎn)生.
對研究人員而言,這些結(jié)果將促進(jìn)人們開發(fā)靶向療法來阻斷TGF-β以便降低放射療法所導(dǎo)致的大腦損傷,和改善發(fā)生認(rèn)知功能下降的老年人體內(nèi)的神經(jīng)元產(chǎn)生.（生物谷Bioon.com）
DOI: 10.1002/emmm.201202197
PMC:
PMID:
Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain
Jose R. Pineda1,2,3,4,Mathieu Daynac1,2,3,4,Alexandra Chicheportiche1,2,3,4,Arantxa Cebrian-Silla5,Karine Sii Felice1,2,3,4,Jose Manuel Garcia-Verdugo5,Fran?ois D. Boussin1,2,3,4,?,*,Marc-André Mouthon1,2,3,4,?,*
Neurogenesis decreases during aging and following cranial radiotherapy, causing a progressive cognitive decline that is currently untreatable. However, functional neural stem cells remained present in the subventricular zone of high dose-irradiated and aged mouse brains. We therefore investigated whether alterations in the neurogenic niches are perhaps responsible for the neurogenesis decline. This hypothesis was supported by the absence of proliferation of neural stem cells that were engrafted into the vascular niches of irradiated host brains. Moreover, we observed a marked increase in TGF-β1 production by endothelial cells in the stem cell niche in both middle-aged and irradiated mice. In co-cultures, irradiated brain endothelial cells induced the apoptosis of neural stem/progenitor cells via TGF-β/Smad3 signalling. Strikingly, the blockade of TGF-β signalling in vivo using a neutralizing antibody or the selective inhibitor SB-505124 significantly improved neurogenesis in aged and irradiated mice, prevented apoptosis and increased the proliferation of neural stem/progenitor cells. These findings suggest that anti-TGF-β-based therapy may be used for future interventions to prevent neurogenic collapse following radiotherapy or during aging.
