Reducing ADAMTS-3 Inhibits Amyloid β Deposition in App Knock-in Mouse.

Abstract

Reelin is a secreted protein that antagonizes the deposition and toxicity of amyloid β peptide (Aβ). Therefore, augmentation of Reelin activity may ameliorate Alzheimer's disease (AD). We have recently reported that a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS-3) cleaves and inactivates Reelin in the mouse brain. In the present study, we investigated the effect of reducing ADAMTS-3 on deposition of Aβ by crossbreeding drug-inducible ADAMTS-3 conditional knock-out (cKO) mice with "next-generation" AD model mice. We found that reducing ADAMTS-3 inhibited deposition of Aβ significantly in AppNL-F mice, which produce human wild-type Aβ. On the other hand, reducing ADAMTS-3 had no effect in AppNL-G-F mice, which produce the Arctic mutant Aβ (E22G) that forms protofibrils more efficiently than does wild-type Aβ. Thus, the findings suggest that the administration of an inhibitor against ADAMTS-3 will prevent the progression of AD pathology caused by deposition of wild-type Aβ.