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J Alzheimers Dis. 2016 Oct 4;54(3):1193-1205.

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

Author information

1
Cell Signaling Laboratory, Cell and Molecular Biology Department, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Chile.
2
Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile.
3
Laboratorio Bionanotecnologia, Facultad de Salud, Universidad Bernardo O Higgins, Chile.
4
Department of Neurology, School of Medicine, Pontificia Universidad Católica de Chile, Chile.
5
National Center for Advancing Translational Science (NACTS), NIH, Bethesda, MD, USA.
6
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, University of Texas Medical School at Houston, Houston, TX, USA.
7
Gastroentorology Department, School of Medicine, Pontificia Universidad Católica de Chile, Chile.
8
Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Australia.
9
Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Chile.

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; PMCA; amyloid-beta peptide; amyloid-beta protein precursor; c-Abl tyrosine kinase; imatinib; oligomers

PMID:
27567806
DOI:
10.3233/JAD-151087
[Indexed for MEDLINE]

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