Late-Onset Alzheimer's disease (LOAD) is biochemically characterized by abnormal elevations of AB peptide and increased tau phosphorylation. Recently, reduced activity ofthe Retromer complex, which is important for the recycling of transmembrane receptors from endosomes to the Trans-Golgi Network (TGN), has been implicated in the pathology of LOAD from human patient expression profiling. The importance of retromer trafficking to LOAD is supported by several studies including both mouse and Drosophila genetic models of retromer deficiency, which have increased levels of Ap peptide, neurological deficits, and in the fly, extensive neurodegeneration. Defective retromer trafficking also inhibits Wnt signaling, suggesting a pathway via glycogen synthase kinase 3 beta (GSKSp) through which retromer could alter tau phosphorylation. We hypothesize that defective retromer sorting is central to both elevated AB peptide levels and increased tau phosphorylation in LOAD and that modulating retromer trafficking levels will have a positive impact on neurodegeneration. We will test this hypothesis in transgenic Drosophila models of LOAD where human Amyloid Precursor Protein (APP) and Amyloid Precursor Protein li-secretase (BACE) or human Tau are expressed.
Our specific aims are designed to determine the molecular pathway that connects retromer deficiency to neurodegeneration and characterize novel interacting proteins that could promote retromer stability.

Public Health Relevance

of the proposed research is that given the links between defective retromer activity and Late-Onset Alzheimer's disease, it is essential to understand the molecular regulation of the retromer complex and signaling pathways it modulates in order to pharmacologically intervene and treat LOAD patients

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG008702-24
Application #
8574150
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
24
Fiscal Year
2013
Total Cost
$188,714
Indirect Cost
$70,784
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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