It has recently been shown that anti-amyloid beta peptide (A?) antibodies or agents that bind to and sequester A??in the periphery produce a """"""""sink effect"""""""" in which brain A? levels are appreciably diminished. This peripheral clearance provides the opportunity to develop new strategies for reducing brain A? as a therapeutic treatment in Alzheimer's disease (AD). We propose to develop a novel method for treating AD in which bone marrow stem cells are infected with a lentiviral vector directing expression of the peptidase neprilysin. The infected bone marrow cells are then transplanted to a recipient whereby the recipient will express neprilysin on the surface of red blood cells. Since neprilysin efficiently degrades A?, the serum A? levels will decrease, followed by a decrease in brain A? levels through the """"""""sink effect"""""""". To test this strategy the following specific aims are proposed: (1) to express neprilysin on red blood cells and determine its effect on plasma and brain A? levels and amyloid plaque formation in young amyloid precursor protein transgenic (APP Tg) mice. A lentivirus vector will be used to introduce neprilysin into bone marrow progenitor cells from a donor mouse and transplant these infected cells into a recipient APP Tg mice. Brain and plasma A? levels, neprilysin activity in the plasma, and amyloid plaque formation in the brain will be monitored for up to 18 months. (2) To determine if expression of neprilysin on red blood cells can reverse the number of amyloid plaques in older APP Tg mice.
This aim will be essentially the same as the first except that the recipient mice will be 18-20 months old, and we will determine if clearance of plasma A? can lead to dissolution of preformed amyloid deposits in the brain. ? ? Taken together these studies represent a novel use of stem cells to provide a mechanism for the clearance of peripheral A?, which should lead to clearance of brain A??through a described """"""""sink effect"""""""". This represents a novel and potential useful therapeutic approach for preventing and treating Alzheimer's disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG024899-01
Application #
6845956
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (O1))
Program Officer
Buckholtz, Neil
Project Start
2004-09-15
Project End
2006-06-30
Budget Start
2004-09-15
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$147,300
Indirect Cost
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Liu, Yinxing; Studzinski, Christa; Beckett, Tina et al. (2009) Expression of neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of Alzheimer disease. Mol Ther 17:1381-6
Guan, Hanjun; Liu, Yinxing; Daily, Abigail et al. (2009) Peripherally expressed neprilysin reduces brain amyloid burden: a novel approach for treating Alzheimer's disease. J Neurosci Res 87:1462-73
Liu, Yinxing; Guan, Hanjun; Beckett, Tina L et al. (2007) In vitro and in vivo degradation of Abeta peptide by peptidases coupled to erythrocytes. Peptides 28:2348-55
Yao, Hongbing; Hersh, Louis B (2006) Characterization of the binding of the fluorescent ATP analog TNP-ATP to insulysin. Arch Biochem Biophys 451:175-81
Daily, Abigail; Nath, Avindra; Hersh, Louis B (2006) Tat peptides inhibit neprilysin. J Neurovirol 12:153-60
Shinall, Heather; Song, Eun Suk; Hersh, Louis B (2005) Susceptibility of amyloid beta peptide degrading enzymes to oxidative damage: a potential Alzheimer's disease spiral. Biochemistry 44:15345-50