Identifying new targets for future drugs against AD

Eric Norstrom, PhD
University of Chicago (Chicago, IL)

Mentors

Sangram Sisodia, PhD
University of Chicago (Chicago, IL)
Year Awarded:
2007
Grant Duration:
April 1, 2007 to March 31, 2009
Disease:
Alzheimer's Disease
Award Amount:
$99,431
Grant Reference ID:
A2007622
Award Type:
Postdoctoral Fellowship
Award Region:
US Midwestern

In Vivo Identification of APP-Interacting Proteins

Summary

e aim to generate a transgenic mouse that expresses APP containing a peptide tag. By using this tagged APP as'bait' in the living animal, we can subsequently purify it and those proteins with which it is bound. Analyzing the purified material and comparing it to a protein database will confirm binding partners identified by cell culture studies and identify new binding partners with new specific targets for drug therapy.

Details

Alzheimer's disease is an incurable neurodegenerative disease characterized by the accumulation of amyloid plaques - deposits of protein in the brain whose main constituent is the Ab peptide, which is itself derived from the metabolism of a larger protein called APP. Reducing the Ab load in the brain is a major goal of Alzheimer's research, and to accomplish this, many strategies aim to inhibit the metabolism of APP. Thus, understanding which proteins APP interacts with is important because 1) this aids in the design of small molecule drugs, and 2) if APP metabolism is to be inhibited, an understanding of its natural function is critical. Although many studies have investigated the metabolism of APP in cultured cells, confirmation of these results in animal studies has not yet been achieved. Thus, we aim to generate a transgenic mouse that expresses APP containing a peptide tag. By using this tagged APP as'bait' in the living animal, we can subsequently purify it and those proteins with which it is bound. Analyzing the purified material and comparing it to a protein database will confirm binding partners identified by cell culture studies and identify new binding partners with new specific targets for drug therapy.

Publications

Norstrom E.M., Sisodia S.S. (2008) Exploration of the in vivo interactome of amyloid precursor protein by tandem affinity purification. Program No. 137.22/I2 2008 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2008. Online [conference abstract]

Choi SH, Norstrom E (2007) Moderate reduction of gamma-secretase: is there a therapeutic sweet spot? J Neurosci. 2007 Dec 12;27(50):13579-80

Norstrom EM, Zhang C, Tanzi R, Sisodia SS. (2010) Identification of NEEP21 as a ß-amyloid precursor protein-interacting protein in vivo that modulates amyloidogenic processing in vitro. J Neurosci. 2010 Nov 17;30(46):15677-85. PubMed Icon Google Scholar Icon

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