STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer’s β-amyloid deposits

This study investigated c-Abl inhibitor STI57I (Gleevec) on apoptosis, tau hyperphosphorylation, and behavioral impairments in both rats injected intrahippocampally with Aβ fibrils and in  the APPsw/ PSEN1dE9 AD mouse model. Past studies have shown that the kinase c-Abl plays a central role in neurodegeneration induced in vitro by Aβ fibrils. These fibrils induce increases in c-Abl levels, activity in rat hippocampal neurons, both total and nuclear p73 protein levels, and the p73/c-Abl complex. Consistent with the c-Abl/p73 participation in the pathogenic mechanism of Alzheimer’s disease, it was shown that p73 accumulates in the nucleus of neurons and localizes to neurofibrillary tangles in the Alzheimer’s disease brain. Furthermore, c-Abl phosphorylates tau Tyr394 and is present in pretangle neurons in Alzheimer’s disease brains. Results in this study show that the Aβ-induced pathology in vivo is associated with p73 phosphorylation and changes in the levels of p73 and c-Abl. This study indicates that this signalling pathway has a pathogenic role in Alzheimer’s disease.