The accumulation of amyloid beta-peptide (ABeta) is an early and necessary step in the pathogenesis of Alzheimer's Disease (AD). ABeta is generated from the amyloid beta-protein precursor (APP) by two sequential proteolytic cleavages mediated by beta- and gamma-secretases (20). If the action of these secretases could be impaired, ABeta deposition might decline and, in turn, the pathogenesis of AD could be halted. Our preliminary data suggests that sortilin, a 100kDa neurotensin receptor and putative trafficking molecule, is downregulated in AD patient-derived postmortem brain tissue. Furthermore, suppression of endogenous sortilin in cultured cells, using RNA interference, increases ABeta generation suggesting that sortilin may be a modulatory factor in ABeta biogenesis. In light of our findings, the specific aims of this project include: evaluating the role of sortilin in APP processing and ABeta deposition, determining the relevant protein interactions of sortilin and their subcellular localization, and determining the expression pattern of sortilin in human brain tissue. This is to be accomplished through a variety of techniques, some including: immunofluorescence, subcellular fractionation, RNAi, Western blot, and ELISA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS051957-03
Application #
7385024
Study Section
Special Emphasis Panel (ZRG1-F03A (20))
Program Officer
Sutherland, Margaret L
Project Start
2006-03-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$36,578
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Finan, Gina M; Okada, Hirokazu; Kim, Tae-Wan (2011) BACE1 retrograde trafficking is uniquely regulated by the cytoplasmic domain of sortilin. J Biol Chem 286:12602-16