Bye N, Zieba M, Wreford N G, Nichols N R
Department of Physiology, Monash University, Clayton, Vic., Australia.
Neuroscience. 2001;105(4):853-62. doi: 10.1016/s0306-4522(01)00236-6.
Up-regulation of endogenous neurotrophic factors may protect against apoptosis during ageing. Recent studies showed that the expression of several neurotrophic factors increased with age in specific regions of the rat brain. Previously, we showed that removal of trophic adrenal steroids by adrenalectomy induced apoptosis in the dentate gyrus of adult rats, which was accompanied by increased expression of transforming growth factor-beta1 (TGF-beta1) messenger RNA. In this study, we compared the relative densities of apoptotic cells in the dentate gyrus with TGF-beta1 messenger RNA expression in virgin male Fischer 344 rats ranging from 2 to 26 months of age across three treatment groups: adrenalectomy, adrenalectomy with corticosterone replacement, or sham operation. Seven days after adrenalectomy an increase in the density of apoptotic cells was observed in rats of all age groups compared with sham-operated and corticosterone-treated groups. By in situ hybridisation, the glial messenger RNAs, TGF-beta1 and glial fibrillary acidic protein as a marker of ageing, increased following adrenalectomy in the dentate gyrus in rats of all ages compared with control groups. Interestingly, within adrenalectomy groups, both the number and density of apoptotic cells decreased significantly by 6-8 months with a further decrease at 24-26 months of age. Furthermore, the amount of apoptosis corresponded to changes in TGF-beta1 expression, notably in: (i) adrenalectomised rats showing a significant inverse correlation and (ii) 24-26-month-old rats with the lowest induced apoptosis showing increased expression at the time of adrenalectomy. These studies show that resistance to adrenalectomy-induced apoptosis in the dentate gyrus is associated with increases in TGF-beta1 messenger RNA expression. Furthermore, the endogenous up-regulation of neurotrophic factors, such as the increase in TGF-beta1 expression in the oldest rats, suggests that the aged brain may have compensatory mechanisms, which protect against apoptosis.
内源性神经营养因子的上调可能在衰老过程中保护细胞免受凋亡。最近的研究表明，几种神经营养因子的表达在大鼠脑的特定区域随年龄增加。此前，我们发现肾上腺切除去除营养性肾上腺类固醇会诱导成年大鼠齿状回凋亡，同时伴有转化生长因子-β1（TGF-β1）信使核糖核酸表达增加。在本研究中，我们比较了2至26月龄的未交配雄性Fischer 344大鼠三个治疗组（肾上腺切除、肾上腺切除加皮质酮替代或假手术）齿状回中凋亡细胞的相对密度与TGF-β1信使核糖核酸表达。肾上腺切除术后7天，与假手术组和皮质酮治疗组相比，所有年龄组大鼠的凋亡细胞密度均增加。通过原位杂交，与对照组相比，所有年龄大鼠肾上腺切除术后齿状回中作为衰老标志物的神经胶质信使核糖核酸、TGF-β1和神经胶质纤维酸性蛋白均增加。有趣的是，在肾上腺切除组中，凋亡细胞的数量和密度在6 - 8个月时显著下降，在24 - 26月龄时进一步下降。此外，凋亡量与TGF-β1表达变化相对应，特别是在：（i）肾上腺切除大鼠中显示出显著负相关，以及（ii）诱导凋亡最低的24 - 26月龄大鼠在肾上腺切除时表达增加。这些研究表明，齿状回对肾上腺切除诱导凋亡的抗性与TGF-β1信使核糖核酸表达增加有关。此外，神经营养因子的内源性上调，如最年长大鼠中TGF-β1表达的增加，表明衰老大脑可能具有防止凋亡的补偿机制。
