DENDRITIC TRANSLOCATION OF RC3 NEUROGRANIN MESSENGER-RNA IN NORMAL AGING, ALZHEIMER-DISEASE AND FRONTOTEMPORAL DEMENTIA/

RC3/neurogranin is a postsynaptic protein kinase C (PKC)-/calmodulin-b inding substrate implicated in long-term potentiation (LTP) forms of s ynaptic plasticity. Our previous digoxigenin in situ hybridization (DI G-ISH) studies detected RC3 mRNA in apical dendrites and cell bodies o f neurons in the rat cerebral cortex and hippocampus. This observation suggested that RC3 mRNA is selectively translocated to dendrites, whe re it may be translated locally in response to synaptic activity. To t est this hypothesis further, we isolated a full-length cDNA clone of t he homologous human RC3 mRNA from a human cortex lambda GT11 library, determined its nucleotide and predicted amino acid sequences, and perf ormed mRNA expression studies in cerebral cortex from normal human pat ients and from patients with Alzheimer disease (AD) and fronto-tempora l dementia (FTD). The human cDNA clone detects a single approximate to 1.3 kb mRNA whose nucleotide sequence is 73% similar to the rat nucle otide sequence and 96% similar to its amino acid sequence. DIG-ISH stu dies detect robust staining of RC3 mRNA in cell bodies of numerous neu rons throughout Layers TT-VI and in both apical and basal dendrites of pyramidal neurons in human neocortex (temporal/frontal). We conclude that dendritic targeting of RC3 mRNA is conserved in human brain. In A D neocortex tissue, there is little or no evidence for RC3 mRNA transl ocation to dendrites, while in FTD neocortex, targeting of RC3 mRNA to apical dendrites is preserved. Comparative studies in AD and FTD poin t to the potential importance of synapse integrity and the dendritic c ytoskeleton in RC3 mRNA targeting in the human neocortex.