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 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.