title: Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease.
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.
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.|Drug Discovery Laboratory, Department of Neurology & Easton Center for AD Research, University of California, Los Angeles, CA, USA.
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Spilman
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.|Apoptosis, Cancer and Development Laboratory, University of Lyon Cancer Center, Centre Léon Bérard, Lyon, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Corset
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Gorostiza
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Poksay
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Galvan
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Junli
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Rammohan
authors.initials: R
authors.lastname: Rao
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Clare
authors.initials: C
authors.lastname: Peters-Libeu
authors.affiliation: Biomarin Pharmaceuticals, Novato, CA, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Vincelette
authors.affiliation: Biomarin Pharmaceuticals, Novato, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: McGeehan
authors.affiliation: Biomarin Pharmaceuticals, Novato, CA, USA.
authors.forename: Melita
authors.initials: M
authors.lastname: Dvorak-Ewell
authors.affiliation: Laboratory for Translational Neuroscience Research, Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Janine
authors.initials: J
authors.lastname: Beyer
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.|Drug Discovery Laboratory, Department of Neurology & Easton Center for AD Research, University of California, Los Angeles, CA, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Campagna
authors.affiliation: Laboratory for Translational Neuroscience Research, Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Krystof
authors.initials: K
authors.lastname: Bankiewicz
authors.affiliation: Apoptosis, Cancer and Development Laboratory, University of Lyon Cancer Center, Centre Léon Bérard, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.|Drug Discovery Laboratory, Department of Neurology & Easton Center for AD Research, University of California, Los Angeles, CA, USA.
authors.forename: Varghese
authors.initials: V
authors.lastname: John
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.|Drug Discovery Laboratory, Department of Neurology & Easton Center for AD Research, University of California, Los Angeles, CA, USA.
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000523:psychology / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D032701:Biomimetics; D045744:Cell Line, Tumor; D003071:Cognition / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008570:Memory, Short-Term / Q000502:physiology; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism*; D000075388:Netrin-1; D010865:Pilot Projects; D051381:Rats; D021641:Recognition, Psychology / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D000072197:ADAM10 Protein
keywords: Aβ1-42; AβPP; CED; amplification; inducible; mimetic; netrin-1; sAβPPα