Brain-derived neurotrophic factor is reduced in Alzheimer's disease
Introduction
Brain-derived neurotrophic factor (BDNF) is a member of the structurally and functionally homologous neurotrophic family which also consists of nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophic factor-4/5 (NT-4/5). BDNF mRNA and protein levels have been detected in the hippocampus, amygdala, projection areas of the olfactory system, inner and outer pyramidal layers of the neocortex, claustrum, cerebellum and the superior colliculus 21, 23, 28, 35, 56, 64, 70, 75, 76suggesting that BDNF has a more widespread distribution than NGF. Within both the rat and human hippocampus, BDNF mRNA and protein levels have been visualized in the hilar region of the dentate gyrus and the pyramidal and apical dendritic processes of the CA3, CA2, CA1 and subiculum regions 21, 64, 79.
Members of the neurotrophin family have been proposed to play a role in the protection of specific neuronal populations by suppressing the expression of `suicide genes' which, when activated are involved in the process of programmed cell death 2, 32, 60. BDNF has been observed to either stimulate the differentiation or enhance the survival of cholinergic neurons both in vitro 37, 48and in vivo [41]. In the adult rat brain, hippocampal damage has been reported to up-regulate BDNF mRNA expression within injury-resistant regions of the hippocampus 6, 12, 13, 27, 38, 45, 62, 71, 73. Furthermore, BDNF has been reported to increase the survival of basal forebrain cholinergic neurons after fimbrial transection [54]and excitotoxic lesioning [11]. The administration of rhBDNF to rats after fimbrial transection has been observed to result in a reduction in axotomy-induced degeneration of the basal forebrain cholinergic neurons [37]and to induce the sprouting of cholinergic processes within the residual hippocampal neurons ipsilateral to the lesion [11]. The observed trophic effects of BDNF on several different neuronal populations after brain insults has lead to the suggestion that BDNF may have a protective effect on neuronal systems in neurodegenerative disorders such as Alzheimer's disease. Alzheimer's disease is a degenerative disorder of the central nervous system characterized by senile plaques, neurofibrillary tangles and β-amyloid deposition. Selective neuronal loss occurs in Alzheimer's disease in the areas of the nucleus basalis of Meynert, locus coeruleus, hippocampus, amygdala, and neocortical association areas 17, 50. It has been proposed that Alzheimer's disease pathology may be due to a deficit in neurotrophin protein or receptor expression 3, 25. While there is little evidence supporting this proposal, a reduction in BDNF mRNA expression has been observed in human post-mortem Alzheimer's disease hippocampi when compared to normal hippocampal levels 54, 63.
While the level of BDNF mRNA expression in the human post-mortem Alzheimer's disease hippocampus has been examined, it has not been investigated whether this observed alteration in BDNF expression also occurs at the protein level. Using a polyclonal antibody directed against the BDNF polypeptide, we compared the level of BDNF protein in human post-mortem Alzheimer's disease and neurologically normal hippocampal and temporal cortex sections using immunohistochemistry techniques.
Section snippets
Human post-mortem brain tissue
All studies using human tissue were performed under approval from the University of Auckland Human Ethical Committee. The normal and Alzheimer's disease brain tissue used in this study were obtained from the New Zealand Neurological Foundation Human Brain Bank in the Department of Anatomy, University of Auckland. Alzheimer's disease brain tissue under went pathological examination to confirm clinical diagnosis based on the CERAD neuropathological protocol [52]. Alzheimer's disease cases were
BDNF immunohistochemistry
The level of BDNF immunoreactivity was examined in regions of the neurologically normal (n=8) and Alzheimer's disease (n=9) hippocampus and temporal cortex using a polyclonal antibody directed against BDNF. In normal human hippocampal sections, a high level of diffuse BDNF immunostaining was observed in the hilar region of the dentate gyrus. In addition BDNF-immunopositive cell bodies were detected within the granule cell layer of the dentate gryus. In the CA3 and CA1 regions of the normal
Discussion
This study examined whether an alteration in BDNF expression occurred at the protein level in the human post-mortem Alzheimer's disease hippocampus and temporal cortex using immunohistochemical techniques. The results of this study revealed a reduction in both the number of BDNF-immuopositive neurons and the intensity of immunostaining within cell bodies in the Alzheimer's disease hippocampus and temporal cortex when compared to the normal human brain. The specificity of the BDNF primary
Acknowledgements
This research was supported by the New Zealand Neurological Foundation, The Health Research Council of New Zealand, the New Zealand Lotteries Health Board and the Auckland University Research Committee. Bronwen Connor holds a Health Research Council of New Zealand Postgraduate Scholarship.
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