The role of neurotrophic factors in neurodegenerative disorders of the human brain

Abstract

Neurotrophic factors are a family of polypeptides that promote the differentiation, growth and survival of numerous central nervous system neurons during development and adulthood. It has been proposed that alterations in neurotrophic factor protein or receptor expression may be involved in the pathogenesis of human neurodegenerative disorders. Recent research supports the therapeutic use of neurotrophic factors in neurodegenerative disorders. However, while information has been obtained regarding the structure and function of neurotrophic factors and their receptors (trk receptors) in the developing and mature rodent central nervous system, little research has been performed examining the expression and functional role of these factors in the normal and diseased human brain. This thesis investigated the role neurotrophic factors and trk receptors play in the pathogenesis of human neurodegenerative disorders. Using immunohistochemical and in situ hybridisation techniques, the regional distribution and cellular localisation of neurotrophic factors and trk receptors was examined throughout both the adult rat and normal human brain. The expression of individual neurotrophic factors and trk receptors was also examined in human post mortem normal, Alzheimer's and Huntington's disease brain tissue, as well as in an animal model of apoptotic nerve cell death. Individual neurotrophic factors exhibited a specific and heterogeneous regional pattern of distribution throughout the adult human brain. Neurotrophic factor expression was detected in several neuronal populations which exhibit selective vulnerability in various neurodegenerative disorders. Alterations in the expression of neurotrophic factors within specific regions of the human brain may result in neuronal atrophy, possibly via apoptotic mechanisms. A significant reduction in the level of brain-derived neurotrophic factor (BDNF) was observed within the hippocampus and temporal cortex of the Alzheimer's disease brain. A loss of neuroprotection afforded by BDNF may contribute to the progressive atrophy of neurons in Alzheimer’s disease. The high-affinity trk receptors, trkA and trkB (full-length and truncated) were also altered within the Alzheimer's disease brain. TrkA receptor-immunoreactivity was observed in astrocytes in the CA1 region of the Alzheimer's disease hippocampus, some of which were associated with β-amyloid plaques. Truncated trkB receptors were found in high levels in senile plaques while the full-length trkB receptor was expressed in glial-like cells in the Alzheimer's disease hippocampus. The appearance of trkA and trkB receptors in astrocytes and plaques in the Alzheimer's disease brain might be related to β-amyloid deposition and could be implicated in the development of Alzheimer's disease. Alterations in insulin-like growth factor-I (IGF-I) protein expression were also observed within the Alzheimer's disease brain. IGF-I-immunoreactivity was expressed in a subpopulation of reactive astrocytes in the Alzheimer's disease temporal cortex. These observations may indicate that IGF-I is involved in the neuropathology of Alzheimer's disease. The induction of IGF-I in response to neuronal injury may be an attempt to inhibit mechanisms that result in delayed neuronal death. In addition, neurotrophic factor expression was examined in the Huntington's disease brain. Glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-α (TGF-α) were significantly reduced within both the Huntington's disease globus pallidus and substantia nigra. Reduced GDNF and TGF- α levels within the Huntington's disease brain may produce a loss of local or target-derived neurotrophic support within the basal ganglia and contribute to the preferential degeneration of medium-sized spiny projection neurons within the Huntington's disease striatum. Moderate hypoxic-ischemic (Hl) injury was used as an animal model of apoptotic nerve cell death. In agreement with the observations made in the Alzheimer's disease brain, moderate Hl injury resulted in the loss of BDNF within the rat hippocampus. In contrast, an increase in trkB (truncated) receptor expression was detected within glial cells in the rat brain. Alterations in BDNF and trkB receptor levels may lead to a loss of neuroprotection and the initiation of downstream mechanisms resulting in the induction of apoptotic processes. A cascade of events similar to those observed within the rat Hl model may occur within human neurodegenerative disorders. This study demonstrated that, while the neuropathogenesis of both Alzheimer's and Huntington's disease is complex, alterations in individual neurotrophic factor or trk receptor expression within selectively vulnerable cortical or subcortical regions may play a role in their pathophysiology. Furthermore, these results support the proposal that neurotrophic factors may be considered for the treatment of neurodegenerative disorders by protecting against neuronal cell loss and by increasing the function of surviving neuronal populations.