Recent studies have shown that inoculation of susceptible mice with amyloid-β (Aβ) peptides accelerates Aβ deposition in the brain, supporting the idea that Aβ may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Aβ may self-amplify, in part, by inhibiting α-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Aβ precursor protein (FL AβPP) and therefore allow greater β-secretase processing, and that Aβ itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PDAβPP mice to exogenous rat Aβ 1 – 40 resulted in increased de novo human Aβ 1 – 42 production and exposure of cells to Aβ decreased production of ADAM10 cleavage product soluble AβPPα (sAβPPα). In a cell-free assay, Aβ decreased ADAM10 cleavage of the chimeric substrate MBP-AβPPC125 and Aβ itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the Aβ 1 – 40-induced Aβ 1 – 42 increase, increased sAβPPα, and reversed the Aβ-induced sAβPPα decrease in vitro. In vivo, induction of netrin-1 expression in PDAβPPSwe/Ind transgenic mice resulted in reductions in both Aβ 1 – 42 and Aβ 1 – 40, and ICV delivery of netrin-1 to PDAβPPSwe/Ind mice increased sAβPPα, decreased Aβ, and improved working memory. Finally, to support further study of netrin-1’s potential as a therapeutic for Alzheimer’s disease, pilot gene therapy studies were performed and a netrin mimetic peptide synthesized and tested that, like netrin, can increase sAβPPα and decrease Aβ 1 – 42in vitro. Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it.

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