Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease
Résumé
Recent studies have shown that inoculation of susceptible mice with amyloid-beta (Abeta) peptides accelerates Abeta deposition in the brain, supporting the idea that Abeta may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Abeta may self-amplify, in part, by inhibiting alpha-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Abeta precursor protein (FL AbetaPP) and therefore allow greater beta-secretase processing, and that Abeta itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PDAbetaPP mice to exogenous rat Abeta1- 40 resulted in increased de novo human Abeta1-42 production and exposure of cells to Abeta decreased production of ADAM10 cleavage product soluble AbetaPPalpha (sAbetaPPalpha). In a cell-free assay, Abeta decreased ADAM10 cleavage of the chimeric substrate MBP-AbetaPPC125 and Abeta itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the Abeta1- 40-induced Abeta1-42 increase, increased sAbetaPPalpha, and reversed the Abeta-induced sAbetaPPalpha decrease in vitro. In vivo, induction of netrin-1 expression in PDAbetaPPSwe/Ind transgenic mice resulted in reductions in both Abeta1-42 and Abeta1- 40, and ICV delivery of netrin-1 to PDAbetaPPSwe/Ind mice increased sAbetaPPalpha, decreased Abeta, 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 sAbetaPPalpha and decrease Abeta1-42in vitro. Taken together, these data provide mechanistic insights into Abeta self-amplification and the ability of netrin-1 to disrupt it
Mots clés
Nerve Growth Factor
Mice
methods
Nerve Growth Factors
Peptides
physiology
ADAM10 Protein
Aging
Alzheimer Disease
Amyloid beta-Protein Precursor
Animal
Animals
Apoptosis
Biomimetics
Brain
Cell Line
Cells
Cognition
Culture
Dependovirus
Disease Models
Drug Discovery
France
Genetic Therapy
Genetic Vectors
genetics
Growth
Humans
Laboratories
Memory
metabolism
psychology
Rats
Recognition (Psychology)
Recombinant Proteins
surgery
Short-Term
Pilot Projects
Proteins
therapy
Transgenic
Tumor
Tumor Suppressor Proteins