BRAIN-DERIVED NEUROTROPHIC FACTOR: mRNA AND PROTEIN LEVELS IN NORMAL AND ALZHEIMER’S DISEASED BRAIN

Abstract

Alzheimer's disease is a progressive neurodegenerative disorder of the central nervous system. One pathological characteristic is excessive neuronal loss in specific regions of the brain. Among the areas most severely affected are the basal forebrain cholinergic neurons and their projection regions, the hippocampus and cortex. Neurotrophic factors, particularly the neurotrophins nerve growth factor and brain-derived neurotrophic factor, play an important role in the development, regulation and survival of basal forebrain cholinergic neurons. Furthermore, brain-derived neurotrophic factor regulates the function of hippocampal and cortical neurons. Neurotrophins are synthesized in hippocampus and cortex and retrogradely transported to the basal forebrain. Decreased levels of neurotrophic factors are suspected to be involved in the neurodegenerative changes observed in Alzheimer's disease. We examined autopsied parietal cortex, hippocampus and nucleus basalis of Meynert samples from age- and gender-matched Alzheimer's diseased and neuro logically non-impaired individuals using the quantitative technique of competitive RT-PCR. We also examined parietal cortex samples by Western blotting. We demonstrate a 3.4-fold decrease in brain-derived neurotrophic factor mRNA levels in the parietal cortex of patients with Alzheimer's disease compared to controls (p < 0.004) but fail to observe changes in BDNF protein levels in that brain region. We also demonstrate, for the first time, BDNF mRNA in the nucleus basalis of Meynert and report an age-related decline in the levels of BDNF mRNA in both control and AD samples. Using the competitive RT-PCR technique we fail to observe differences in BDNF mRNA levels in the hippocampus between AD and control subjects, conflicting with previous in situ hybridization studies and RNase protection assays. A decrease in brain-derived neurotrophic factor synthesis could have detrimental effects on hippocampal, cortical and basal forebrain cholinergic neurons and may account for their selective vulnerability in Alzheimer's disease.