Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease

Recent studies have shown that inoculation of susceptible mice with amyloid-beta (A beta) peptides accelerates A beta deposition in the brain, supporting the idea that A beta may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that A beta may self-amplify, in part, by inhibiting alpha-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length A beta precursor protein (FLA beta PP) and therefore allow greater beta-secretase processing, and that A beta itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PD Lambda beta PP mice to exogenous rat A beta(1-40) resulted in increased de novo human A beta(1-42) production and exposure of cells to A beta decreased production of ADAM10 cleavage product soluble A beta PP alpha (sA beta PP alpha). In a cell-free assay, A beta decreased ADAM10 cleavage of the chimeric substrate MBP-A beta PPC125 and A beta itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the A beta(1-4)0-induced A beta(1-42) increase, increased sA beta PP alpha, and reversed the A beta-induced sA beta PP alpha decrease in vitro. In vivo, induction of netrin-1 expression in PDA beta PPSwe/Ind transgenic mice resulted in reductions in both A beta(1-42) and A beta(1-40), and ICV delivery of netrin-1 to PDA beta PPSwe/Ind mice increased sA beta PP alpha, decreased A beta, 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 sA beta PP alpha and decrease A beta(1-42) in vitro. Taken together, these data provide mechanistic insights into A beta self-amplification and the ability of netrin-1 to disrupt it.