EMBO:放疗或衰老阻断神经干细胞产生神经元机制

改善认知功能发生下降的年老人体内的神经元产生是老龄化社会所面临的一个重要挑战,也是治疗诸如阿尔茨海默病之类的神经退行性疾病的一个主要难题.在一项新的研究中,法国和西班牙研究人员证实利用药物阻断TGF-β分子能够改善小鼠模式动物体内新的神经元产生.相关研究结果发表在2013年4月那期EMBO Molecular Medicine期刊上.这些结果激励人们去开发靶向疗法以便能够改善神经元产生从而阻止老年人认知能力下降和降低放射疗法所导致的大脑损伤.

在成年大脑中,新的神经元有规律地产生以便保证我们的所有认知功能得到维持.这种神经发生过程(neurogenesis)在多种情形下受到不利的影响,特别是在衰老过程中和对脑瘤进行放射疗法之后.根据之前的一些研究,对脑瘤进行放射疗法会导致我们体内储存的神经元数量下降,从而导致认知功能发生不可逆的下降.在衰老过程中,这种认知功能下降同样也会发生.

为此,研究人员一直在研究如何维持神经元库存.他们试图发现哪些因子导致体内神经发生能力下降.他们的初步研究结果表明衰老或高剂量的放疗都不能完全消灭神经干细胞,其中这种干细胞能够产生神经元,因而是神经发生的起源.这些存活下来的神经干细胞位于大脑中的一个特定区域：侧脑室下层(sub-ventricular zone, SVZ),但是它们似乎不能够正常地发挥作用.

研究人员通过进一步的实验发现在放射疗法和衰老这两种情形下,高水平的细胞因子TGF-β(转化生长因子-β)让这些神经干细胞处于休眠状态,从而使得它们容易发生凋亡或者说程序性死亡,进而降低新的神经元数量.

论文通信作者Marc-Andre Mouthon解释道,"我们的研究结论是尽管在衰老期间和在接受高剂量放射疗法之后,神经发生能力下降,但是很多干细胞能够存活几个月的时间并且保持着它们的干性特征."

研究人员还证实利用药物阻断TGF-β能够恢复接受放射疗法的或衰老的小鼠体内新的神经元产生.

对研究人员而言,这些结果将促进人们开发靶向疗法来阻断TGF-β以便降低放射疗法所导致的大脑损伤,和改善发生认知功能下降的老年人体内的神经元产生.

Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain

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.