Peripherally expressed neprilysin reduces brain amyloid burden: a novel approach for treating Alzheimer's disease.
A number of therapeutic strategies for treating Alzheimer's disease have focused on reducing amyloid burden in the brain. Among these approaches, the expression of amyloid beta peptide (Abeta)-degrading enzymes in the brain has been shown to be effective but to date not practical for treating patients. We report here a novel strategy for lowering amyloid burden in the brain by peripherally expressing the Abeta-degrading enzyme neprilysin on leukocytes in the 3xTg-AD mouse model of Alzheimer's disease. Through transplantation of lentivirus-transduced bone marrow cells, the Abeta-degrading protease neprilysin was expressed on the surface of leukocytes. This peripheral neprilysin reduced soluble brain Abeta peptide levels by approximately 30% and lowered the accumulation of amyloid beta peptides by 50-60% when transplantation was performed at both young and early adult age. In addition, peripheral neprilysin expression reduced amyloid-dependent performance deficits as measured by the Morris water maze. Unlike other methods designed to lower Abeta levels in blood, which cause a net increase in peptide, neprilysin expression results in the catabolism of Abeta to small, innocuous peptide fragments. These findings demonstrate that peripherally expressed neprilysin, and likely other Abeta-degrading enzymes, has the potential to be utilized as a therapeutic approach to prevent and treat Alzheimer's disease and suggest that this approach should be explored further.
Guan
Hanjun
H
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA.
Liu
Yinxing
Y
Daily
Abigail
A
Police
Sara
S
Kim
Myung-Hee
MH
Oddo
Salvatore
S
LaFerla
Frank M
FM
Pauly
James R
JR
Murphy
M Paul
MP
Hersh
Louis B
LB
D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D016026:Bone Marrow Transplantation; D001921:Brain / Q000378:metabolism*; D003072:Cognition Disorders / Q000628:therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D016086:Lentivirus; D007962:Leukocytes / Q000378:metabolism*; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic
D016229:Amyloid beta-Peptides; D015260:Neprilysin