Quantification of brain-derived neurotrophic factor expression in the aging monkey brain

While early studies of normal aging largely focused on the loss of neurons as a basis of cognitive aging, current studies of both aging humans and the rhesus monkey model of normal aging demonstrate that forebrain neurons are largely preserved. Instead, MRI and electron microscopic analyses show that age-related changes in the white matter are good predictors of cognitive impairment. White matter changes include an increase in damaged myelin sheaths as well as a loss of myelinated fibers. To explore potential causes of the white matter alterations, the expression of genes related to myelination and axonal survival were examined revealing age-related alterations in the expression of 9 genes in grey matter and 7 in subcortical white matter of the inferior parietal lobule (IPL). Four were selected for further analysis. Of these, brain-derived neurotrophic factor (BDNF) had a statistically significant decrease in expression in the cortical grey matter of the IPL at both the level of gene expression and of protein expression. In 27 male and female rhesus monkeys ranging from young to old, the precursor form of BDNF (proBDNF) was significantly decreased while the mature form was preserved. In order to understand the localization of the age-related decline in proBDNF, immunohistochemical reactivity was quantified in the IPL and in the hippocampus. In the IPL there was a significant decrease in total immunohistochemical reactivity. Further analysis showed that there was an increase in the number of proBDNF positive somata while there was no change in the smaller extrasomal puncta. This increase in cell bodies expressing proBDNF despite the age-related decrease in total proBDNF immunohistochemical density suggests disruption of post-translational processing and/or transport out into the processes. In contrast to the IPL, there was no change in proBDNF density in the hippocampus with age. However, in the hippocampus but not the IPL, proBDNF immunohistochemical reactivity was sexually dimorphic with higher levels in the female monkeys compared to males. While the significance of the change in proBDNF levels for myelin damage is unclear, alteration in this neurotrophin may play a role in the axon loss that accompanies myelin degradation.