Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Alzheimer's Disease Année : 2016

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

Patricia R. Spilman
  • Fonction : Auteur
Veronique Corset
  • Fonction : Auteur
Olivia Gorostiza
  • Fonction : Auteur
Karen S. Poksay
  • Fonction : Auteur
Veronica Galvan
  • Fonction : Auteur
Junli Zhang
  • Fonction : Auteur
Rammohan Rao
  • Fonction : Auteur
Clare Peters-Libeu
  • Fonction : Auteur
Jon Vincelette
  • Fonction : Auteur
Andrew Mcgeehan
  • Fonction : Auteur
Melita Dvorak-Ewell
  • Fonction : Auteur
Janine Beyer
  • Fonction : Auteur
Jesus Campagna
  • Fonction : Auteur
Krystof Bankiewicz
  • Fonction : Auteur
Varghese John
  • Fonction : Auteur
Dale E. Bredesen
  • Fonction : Auteur

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
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Dates et versions

hal-01800005 , version 1 (25-05-2018)

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Patricia R. Spilman, Veronique Corset, Olivia Gorostiza, Karen S. Poksay, Veronica Galvan, et al.. Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease, 2016, 52 (1), pp.223-242. ⟨10.3233/JAD-151046⟩. ⟨hal-01800005⟩
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