Under-expression of Kalirin-7 Increases iNOS Activity in Cultured Cells and Correlates to Elevated iNOS Activity in Alzheimer's Disease Hippocampus 1

Abstract

Recently, it has been reported that Kalirin gene transcripts are under-expressed in AD hippocampal specimens compared to the controls. The Kalirin gene generates a dozen Kalirin isoforms. Kalirin-7 is the predominant protein expressed in the adult brain and plays crucial roles in growth and maintenance of neurons. Yet its role in human diseases is unknown.

We report that Kalirin-7 is significantly diminished both at the mRNA and protein levels in the hippocampus specimens from 19 AD patients compared to the specimens from 15 controls. Kalirin-7 associates with iNOS in the hippocampus, and therefore, Kalirin-7 is complexed with iNOS less in AD hippocampus extracts than in control hippocampus extracts. In cultured cells, Kalirin-7 associates with iNOS and down-regulates the enzyme activity. The down-regulation is attributed to the highly conserved 33 amino acid sequence, K⁶¹⁷-H⁶⁴⁹, of the 1,663 amino acids long Kalirin-7. Remarkably, the iNOS activity is considerably higher in the hippocampus specimens from AD patients than the specimens from 15 controls. These observations suggest that the under-expression of Kalirin-7 in AD hippocampus correlates to the elevated iNOS activity.