Developmental distribution of nerve growth factor and pathological models of expression in the brain
Description
Nerve growth factor (NGF) is vital for the development and survival of specific neuron populations. Scientists have also discovered that the earlier trophic role of NGF revived during injury which serves to protect vulnerable neurons. The realization that NGF can counteract neuronal atrophy and death encouraged researchers to investigate its use for the treatment of various neurodegenerative diseases. However, little is known about the developmental distribution of NGF within the central nervous system (CNS) and the effects of its expression during injury. Understanding the role of NGF expression during development, maturity, and disease is crucial to revealing its therapeutic potential The following dissertation is comprised of three main independent studies. In the first, NGF distribution within the human CNS during fetal development and throughout adulthood was investigated. The results showed that NGF and its high affinity receptor, trkA, are expressed in as early as 19 weeks gestation within the frontal cortex, hippocampus, cerebellar cortex, and basal ganglia. In addition, expression of the low affinity NGF receptor, p75, increases in these regions transiently during fetal development and is significantly reduced post term The second study was designed to determine whether reduced NGF and/or trkA play a role in the pathophysiology of Rett syndrome. The results showed a significant reduction of NGF and trkA within the frontal cortex of Rett patients. In addition, the expression of NGF in the Rett group was significantly related to the presence of cortical astrogliosis. This suggests that while the signals for NGF production during injury remain intact, the critical developmental signals required for early NGF production are impaired In the final study, we sought to determine whether HIV-induced NGF and its receptors trkA and p75 contribute to increased viral load within the brain. Results indicated a direct relationship between HIV antigen levels and NGF/trkA expression. The presence of HIV was also associated with occasional p75 expression in neurons, suggesting that p75 might play a role in mediating neuronal apoptosis In conclusion, these studies demonstrate NGF expression throughout life in several brain regions, and that abnormal expression during development and/or injury results in specific pathological effects