O2–05–02: Inhibition of amyloid precursor protein processing by beta–secretase via site directed antibodies

clearance of amyloid beta peptides by immunological or chemical means as a method of treatment for Alzheimer’s disease (AD). One of the new findings that immerged from these immunological studies was that passive immunization with amyloid beta peptide antibodies resulted in an efflux of amyloid beta peptide from the brain into the plasma (DeMattos et al., Proc Natl Acad Sci USA 98:8850-8855, 2001; DeMattos et al., Science 295: 2264-2267, 2002.) producing what was termed a peripheral “sink effect”. An elegant extension of this “sink effect” concept was described by Matsuoka et al., (J Neurosci. 23:29-33, 2003) who used two amyloid beta peptide-binding compounds, ganglioside GM1 and gelsolin, to bind plasma amyloid beta peptide in hAPP transgenic mice, resulting in a lowering of brain amyloid beta peptide levels by 50% or more. Objective: We have tested the peripheral sink effect using an amyloid peptide degrading enzyme. Methods: We have expressed the amyloid peptide degrading peptidase neprilysin, or an inactive form of neprilysin, on leukocytes in hAPP transgenic mice. Results and Conclusions: Expression of neprilysin activity on leukocytes declined over a four-month period. Mice expressing active neprilysin at two months of age and sacrificed at 7 months of age showed a dramatic decrease in diffuse amyloid deposits in their brain relative to mice expressing inactive neprilysin. These studies demonstrate the use of peripheral neprilysin as a way to prevent amyloid deposition in brain. This work was supported in part by grant AG024899 from the National Institute on Aging.