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

Article type: Research Article

Authors: Spilman, Patricia R.^{a; d; 1} | Corset, Veronique^{a; b; 1} | Gorostiza, Olivia^{a; 3} | Poksay, Karen S.^a | Galvan, Veronica^{a; 4} | Zhang, Junli^{a; 5} | Rao, Rammohan^a | Peters-Libeu, Clare^a | Vincelette, Jon^c | McGeehan, Andrew^c | Dvorak-Ewell, Melita^{c; 6} | Beyer, Janine^e | Campagna, Jesus^{a; d} | Bankiewicz, Krystof^e | Mehlen, Patrick^b | John, Varghese^{a; d; 2} | Bredesen, Dale E.^{a; d; 2; *}

Affiliations: [a] Buck Institute for Research on Aging, Novato, CA, USA | [b] Apoptosis, Cancer and Development Laboratory, University of Lyon Cancer Center, Centre Léon Bérard, Lyon, France | [c] Biomarin Pharmaceuticals, Novato, CA, USA | [d] Drug Discovery Laboratory, Department of Neurology & Easton Center for AD Research, University of California, Los Angeles, CA, USA | [e] Laboratory for Translational Neuroscience Research, Department of Neurological Surgery, University of California, San Francisco, CA, USA

Correspondence: [*] Correspondence to: Dale E. Bredesen, Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, California 94945, USA. Tel.: +1 415 209 2000; E-mail: [email protected].

Note: [1] These two authors contributed equally to this work.

Note: [2] These two authors share senior authorship.

Note: [3] Current location: Biomarin Pharmaceuticals, Novato,California, USA.

Note: [4] Current location: Department of Physiology, The Barshop Institute for Longevity and Aging Studies/Nathan Shock Aging Center, University of Texas Health Science Center, San Antonio, Texas, USA.

Note: [5] Current location: Gladstone Institutes, San Francisco,California, USA.

Note: [6] Current location: Ultragenyx, Novato, California, USA.

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 Aβ1-42 in vitro. Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it.

Keywords: Aβ_1-42, AβPP, amplification, CED, inducible, mimetic, netrin-1, sAβPPα

DOI: 10.3233/JAD-151046

Journal: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 223-242, 2016