Affiliations: [a] Departments of Chemistry, University of Kentucky, Lexington, KY 40506-0055, USA | [b] Departments of Pathology and Neurology, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA | [c] Department of Internal Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305-5440, USA
Correspondence:
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Corresponding author: Tae H. Ji, Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055, USA. Tel.: +1 859 257 3163; Fax: +1 859 257 3229; E-mail: [email protected].
Note: [1] This work was supported by grants RO1 HD18702 and 5P50 AG05144 from the National Institutes of Health. The use of human tissues was approved by the University of Kentucky Institutional Review Board.
Note: [] Communicated by Mark Lovell
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.
