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: Lisbell D Estrada, David Chamorro, María José Yañez, Marcelo Gonzalez, Nancy Leal, Rommy von Bernhardi, Andrés E Dulcey, Juan Marugan, Marc Ferrer, Claudio Soto, Silvana Zanlungo, Nibaldo C Inestrosa, Alejandra R Alvarez
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 54 Issue 3 Pg. 1193-1205 (10 04 2016) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 27567806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-abl

Topics

• Alzheimer Disease (blood, enzymology, pathology)
• Amyloid beta-Peptides (blood)
• Animals
• Cell Line
• Hippocampus (drug effects, metabolism, pathology)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-abl (antagonists & inhibitors, blood)