DIFFERENTIAL REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR AND TYPE-II CALCIUM/CALMODULIN-DEPENDENT PROTEIN-KINASE MESSENGER-RNA EXPRESSION IN ALZHEIMERS-DISEASE

The relative levels of messenger RNA for brain-derived neurotrophic factor and the a subunit of calcium/calmodulin-dependent protein kinase type II were examined in hippocampal sections from Alzheimer's diseased and age matched non-diseased brains by in situ hybridization histochemistry. Consistent with previous reports in monkey and rodent, calcium/calmodulin-dependent protein kinase II messenger RNA was prevalent throughout the dentate gyrus, all the principal hippocampal subfields, and adjacent cortical regions. A distribution consistent with the dendritic localization of calcium/calmodulin-dependent protein kinase II was also observed. In contrast, brain-derived neurotrophic factor messenger RNA levels were much lower than calcium/calmodulin-dependent protein kinase,II messenger RNA levels and were less widely distributed. Within the hippocampus of Alzheimer's diseased brains, levels of calcium/calmodulin-dependent protein kinase II messenger RNA were increased and levels of brain-derived neurotrophic factor messenger RNA were decreased in comparison with matched controls. These changes were consistently seen in four out of six cases processed for both messenger RNA species and ranged from 150-300% relative to non-diseased brain tissue for calcium/calmodulin-dependent protein kinase II and 20-70% for brain-derived neurotrophic factor. These results suggest that within the Alzheimer's hippocampus an altered program of gene expression is occurring leading to aberrant levels of both calcium/carmodulin-dependent protein kinase II and brain-derived neurotrophic factor messenger RNA, Previous studies of the activity-dependent regulation of these messenger RNA species suggest these results are consistent with a decrease in afferent activity within the Alzheimer's hippocampus.