Reduction of Blood Amyloid-β Oligomers in Alzheimer’s Disease Transgenic Mice by c-Abl Kinase Inhibition

Article type: Research Article

Authors: Estrada, Lisbell D.^{a; b; c} | Chamorro, David^a | Yañez, María José^a | Gonzalez, Marcelo^a | Leal, Nancy^a | von Bernhardi, Rommy^d | Dulcey, Andrés E.^e | Marugan, Juan^e | Ferrer, Marc^e | Soto, Claudio^f | Zanlungo, Silvana^g | Inestrosa, Nibaldo C.^{b; h; i} | Alvarez, Alejandra R.^{a; b; *}

Affiliations: [a] Cell Signaling Laboratory, Cell and Molecular Biology Department, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Chile | [b] Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile | [c] Laboratorio Bionanotecnologia, Facultad de Salud, Universidad Bernardo O Higgins, Chile | [d] Department of Neurology, School of Medicine, Pontificia Universidad Católica de Chile, Chile | [e] National Center for Advancing Translational Science (NACTS), NIH, Bethesda, MD, USA | [f] Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, University of Texas Medical School at Houston, Houston, TX, USA | [g] Gastroentorology Department, School of Medicine, Pontificia Universidad Católica de Chile, Chile | [h] Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Australia | [i] Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Chile

Correspondence: [*] Correspondence to: Dr. Alejandra Alvarez. Pontificia Universidad Católica de Chile, Portugal 49, Santiago 830025, Chile. Tel.: +56 226862926; Fax: +56 226862959; E-mail: [email protected].

Abstract: One of the pathological hallmarks of Alzheimer’s disease (AD) is the presence of amyloid plaques, which are deposits of misfolded and aggregated amyloid-beta peptide (Aβ). The role of the c-Abl tyrosine kinase in Aβ-mediated neurodegeneration has been previously reported. Here, we investigated the therapeutic potential of inhibiting c-Abl using imatinib. We developed a novel method, based on a technique used to detect prions (PMCA), to measure minute amounts of misfolded-Aβ in the blood of AD transgenic mice. We found that imatinib reduces Aβ-oligomers in plasma, which correlates with a reduction of AD brain features such as plaques and oligomers accumulation, neuroinflammation, and cognitive deficits. Cells exposed to imatinib and c-Abl KO mice display decreased levels of β-CTF fragments, suggesting that an altered processing of the amyloid-beta protein precursor is the most probable mechanism behind imatinib effects. Our findings support the role of c-Abl in Aβ accumulation and AD, and propose AD-PMCA as a new tool to evaluate AD progression and screening for drug candidates.

Keywords: Alzheimer’s disease, amyloid-beta peptide, amyloid-beta protein precursor, c-Abl tyrosine kinase, imatinib, oligomers, PMCA

DOI: 10.3233/JAD-151087

Journal: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1193-1205, 2016