[Molecular mechanisms for the development and aging of the primate central nervous system]

The central nervous system (CNS) of primates, including humans, is more complex than the CNS of other mammals. In particular, the cerebral cortex expands during evolution and this has resulted in the emergence of higher cognitive abilities in primates. Recent neurochemical and neuroanatomical methods have clarified the presence of various neuroactive substances including neuropeptides, neurotrophic factors and growth associated proteins in the developing mammalian cerebral cortex. Among these signal molecules, we have focused on somatostatin (SRIF), neurotrophins (BDNF, NT-4/5 and NT-3) and their receptors (Trk), growth associated proteins such as GAP-43 and SCG-10 during the development and aging of primate CNS. We found that although full-length TrkB, a high affinity receptor for BDNF and NT4/5, was detected from the embryonic stage to adulthood, the level of truncated TrkB which lacks tyrosine kinase domain, only increased after birth. This development of truncated TrkB correlated well with down-regulation in the gene expression of GAP-43 and SCG-10. The reductions of GAP-43 and SCG-10 may result in the elimination of callosal axons in the monkey cerebral cortex after birth. The highest levels of BDNF protein in the various cerebral cortices occurred between postnatal 1 and 6 when the number of synapses is highest. In contrast, there was no transient increase in the levels of NT4/5 or NT3 after birth. These findings suggest that BDNF is one of the candidates for the synaptic development of the primate cerebral cortex. During aging processes, we observed decreases in the levels of SRIF and BDNF mRNAs in the cerebral cortex. Since BDNF is an upstream gene expression molecule of SRIF, the decline of SRIF mRNA during aging may be due to the decrease in the gene expression of BDNF. Similar reductions of gene expressions of SRIF and BDNF in the brains of the patients with Alzheimer's disease, suggest that aged monkeys are good model animals for these neuro-degenerative diseases.