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

J Alzheimers Dis. 2016 Mar 8;52(1):223-42. doi: 10.3233/JAD-151046.

Abstract

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 Aβ1- 40 resulted in increased de novo human Aβ1-42 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 Aβ1- 40-induced Aβ1-42 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 Aβ1-42 and Aβ1- 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 Aβ1-42in vitro. Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it.

Keywords: Aβ1-42; AβPP; CED; amplification; inducible; mimetic; netrin-1; sAβPPα.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / metabolism
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / psychology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Biomimetics
  • Cell Line, Tumor
  • Cognition / physiology
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Humans
  • Memory, Short-Term / physiology
  • Mice, Transgenic
  • Nerve Growth Factors / genetics*
  • Nerve Growth Factors / metabolism*
  • Netrin-1
  • Pilot Projects
  • Rats
  • Recognition, Psychology / physiology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • NTN1 protein, human
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Ntn1 protein, rat
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Netrin-1
  • ADAM10 Protein