期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 87, 期 6, 页码 1462-1473出版社
WILEY
DOI: 10.1002/jnr.21944
关键词
gene therapy; peptidases; amyloid clearance
资金
- NCRR NIH HHS [P20RR02017] Funding Source: Medline
- NIA NIH HHS [AG 24899, R21 AG024899] Funding Source: Medline
- NIDA NIH HHS [R01 DA002243, DA 02243, R01 DA002243-30A1] Funding Source: Medline
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 (A beta)-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 A beta-degrading enzyme neprilysin on leukocytes in the 3xTg-AD mouse model of Alzheimer's disease. Through transplantation of lentivirus-transduced bone marrow cells, the A beta-degrading protease neprilysin was expressed on the surface of leukocytes. This peripheral neprilysin reduced soluble brain A beta peptide levels by similar to 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 A beta levels in blood, which cause a net increase in peptide, neprilysin expression results in the catabolism of A beta to small, innocuous peptide fragments. These findings demonstrate that peripherally expressed neprilysin, and likely other A beta-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. (C) 2008 Wiley-Liss, Inc.
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