Author

Evert Njomen

Date Approved

3-12-2014

Date Posted

4-7-2014

Degree Type

Campus Only Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

Committee Member

Hedeel Evans, Ph.D., Chair

Committee Member

Deborah Heyl-Clegg, Ph.D.

Committee Member

Steven Pernecky, Ph.D.

Abstract

Nuclear translocation of IGFBP3 by importin β1 is a prerequisite for apoptosis induced by IGFBP3 in Alzheimer’s disease (AD). The neuroprotective peptide humanin (HN) counteracts this IGFBP3-induced cell death. Unfortunately, the natural synthesis of this peptide decreases with age coincident with the time that people are likely to develop AD. In addition, the precise mechanism of action of HN is currently unknown. We have synthesized residues 3 to19 of HN known to be sufficient for its neuroprotective function by solid phase peptide synthesis. Using competitive ligand dot blotting and co-immunoprecipitation, we show here that this 17 amino acid peptide interferes with importin β1 binding to IGFBP3 in vitro, suggesting a possible mechanism of action as an inhibitor of IGFBP3 nuclear translocation, blocking apoptosis. Future work will examine whether the decline in cell death due to HN is accompanied by a corresponding decrease of the nuclear accumulation of IGFBP3 in vivo.

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