TY - JOUR
T1 - Peripherally expressed neprilysin reduces brain amyloid burden
T2 - A novel approach for treating Alzheimer's disease
AU - Guan, Hanjun
AU - Liu, Yinxing
AU - Daily, Abigail
AU - Police, Sara
AU - Kim, Myung Hee
AU - Oddo, Salvatore
AU - LaFerla, Frank M.
AU - Pauly, James R.
AU - Murphy, M. Paul
AU - Hersh, Louis B.
PY - 2009/5/1
Y1 - 2009/5/1
N2 - 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 β peptide (Aβ)-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 Aβ-degrading enzyme neprilysin on leukocytes in the 3×Tg-AD mouse model of Alzheimer's disease. Through transplantation of lentivirus-transduced bone marrow cells, the Aβ-degrading protease neprilysin was expressed on the surface of leukocytes. This peripheral neprilysin reduced soluble brain Aβ peptide levels by ∼30% and lowered the accumulation of amyloid β 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 Aβ levels in blood, which cause a net increase in peptide, neprilysin expression results in the catabolism of Aβ to small, innocuous peptide fragments. These findings demonstrate that peripherally expressed neprilysin, and likely other Aβ-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.
AB - 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 β peptide (Aβ)-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 Aβ-degrading enzyme neprilysin on leukocytes in the 3×Tg-AD mouse model of Alzheimer's disease. Through transplantation of lentivirus-transduced bone marrow cells, the Aβ-degrading protease neprilysin was expressed on the surface of leukocytes. This peripheral neprilysin reduced soluble brain Aβ peptide levels by ∼30% and lowered the accumulation of amyloid β 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 Aβ levels in blood, which cause a net increase in peptide, neprilysin expression results in the catabolism of Aβ to small, innocuous peptide fragments. These findings demonstrate that peripherally expressed neprilysin, and likely other Aβ-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.
KW - Amyloid clearance
KW - Gene therapy
KW - Peptidases
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U2 - 10.1002/jnr.21944
DO - 10.1002/jnr.21944
M3 - Article
C2 - 19021293
AN - SCOPUS:65549114145
SN - 0360-4012
VL - 87
SP - 1462
EP - 1473
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
IS - 6
ER -