Reduction Of Blood Amyloid-Beta Oligomers In Alzheimer'S Disease Transgenic Mice By C-Abl Kinase Inhibition

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 (A beta). The role of the c-Abl tyrosine kinase in A beta-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-A beta in the blood of AD transgenic mice. We found that imatinib reduces A beta-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 beta-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 A beta accumulation and AD, and propose AD-PMCA as a new tool to evaluate AD progression and screening for drug candidates.