Resistance of the dentate gyrus to induced apoptosis during ageing is associated with increases in transforming growth factor-beta1 messenger RNA.

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.