A new brain‐derived neurotrophic factor transcript and decrease inbrain‐derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer's disease parietal cortex
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AbstractBrain‐derived neurotrophic factor (BDNF) supports hippocampal, cortical and basal forebrain cholinergic neurons, which lose function in Alzheimer's disease. In Alzheimer's tissues such as hippocampus and parietal cortex, brain‐ derived neurotrophic factor mRNA is decreased three‐ to four‐fold compared with controls. However, the molecular mechanism of the down‐regulation of BDNF in Alzheimer's disease is unknown. The human brain‐derived neurotrophic factor gene has multiple promoters governing six non‐coding upstream exons that are spliced to one downstream coding exon, leading to six different transcripts. Here we report an alternate human splice variant within exon 4I for a total of seven transcripts. Previous brain‐derived neurotrophic factor mRNA measurements in Alzheimer's disease tissue were done using the downstream coding exon present in all transcripts. Using RT‐PCR primers specific for each upstream exon, we observe a significant decrease in three human brain‐derived neurotrophic factor mRNA transcripts in Alzheimer's disease samples compared with controls. Transcripts 1 and 3 each exhibit a two‐fold decrease, and transcript 2 shows a five‐fold decrease. There are no significant differences between control and Alzheimer's disease samples for the other transcripts, including the new splice variant. In rat, both transcripts 1 and 3 are regulated through the transcription factor cAMP response element binding protein, whose phosphorylation is decreased in the Alzheimer's disease brain. This could lead to specific down‐regulation of the brain‐derivedneurotrophic factor transcripts shown here.
