title: Reduction of Blood Amyloid-β Oligomers in Alzheimer's Disease Transgenic Mice by c-Abl Kinase Inhibition.
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.
authors: Cell Signaling Laboratory, Cell and Molecular Biology Department, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Chile.|Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile.|Laboratorio Bionanotecnologia, Facultad de Salud, Universidad Bernardo O Higgins, Chile.
authors: Lisbell D
authors: LD
authors: Estrada
authors: Cell Signaling Laboratory, Cell and Molecular Biology Department, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Chile.
authors: David
authors: D
authors: Chamorro
authors: Cell Signaling Laboratory, Cell and Molecular Biology Department, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Chile.
authors: María José
authors: MJ
authors: Yañez
authors: Cell Signaling Laboratory, Cell and Molecular Biology Department, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Chile.
authors: Marcelo
authors: M
authors: Gonzalez
authors: Cell Signaling Laboratory, Cell and Molecular Biology Department, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Chile.
authors: Nancy
authors: N
authors: Leal
authors: Department of Neurology, School of Medicine, Pontificia Universidad Católica de Chile, Chile.
authors: Rommy
authors: R
authors: von Bernhardi
authors: National Center for Advancing Translational Science (NACTS), NIH, Bethesda, MD, USA.
authors: Andrés E
authors: AE
authors: Dulcey
authors: National Center for Advancing Translational Science (NACTS), NIH, Bethesda, MD, USA.
authors: Juan
authors: J
authors: Marugan
authors: National Center for Advancing Translational Science (NACTS), NIH, Bethesda, MD, USA.
authors: Marc
authors: M
authors: Ferrer
authors: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, University of Texas Medical School at Houston, Houston, TX, USA.
authors: Claudio
authors: C
authors: Soto
authors: Gastroentorology Department, School of Medicine, Pontificia Universidad Católica de Chile, Chile.
authors: Silvana
authors: S
authors: Zanlungo
authors: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile.|Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Australia.|Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Chile.
authors: Nibaldo C
authors: NC
authors: Inestrosa
authors: Cell Signaling Laboratory, Cell and Molecular Biology Department, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Chile.|Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile.
authors: Alejandra R
authors: AR
authors: Alvarez
mesh_terms: D000544:Alzheimer Disease / Q000097:blood* / Q000201:enzymology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood*; D000818:Animals; D002460:Cell Line; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000097:blood*
chemical_list: D016229:Amyloid beta-Peptides; D047428:Protein Kinase Inhibitors; D016315:Proto-Oncogene Proteins c-abl
keywords: Alzheimer’s disease; PMCA; amyloid-beta peptide; amyloid-beta protein precursor; c-Abl tyrosine kinase; imatinib; oligomers