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

• Published in: Brain (London, England : 1878) England : 1878), 2008-09, Vol.131 (9), p.2425-2442
• Main Authors: Cancino, Gonzalo I., Toledo, Enrique M., Leal, Nancy R., Hernandez, Diego E., Yévenes, L. Fernanda, Inestrosa, Nibaldo C., Alvarez, Alejandra R.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - chemically induced; Alzheimer Disease - metabolism; Alzheimer Disease - prevention & control; Alzheimer Disease - psychology; Alzheimer's disease; Amyloid beta-Peptides; amyloid β-peptide; Animals; Apoptosis - drug effects; behavioural impairments; Benzamides; c-Abl; Cells, Cultured; Disease Models, Animal; DNA-Binding Proteins - metabolism; Hippocampus - drug effects; Hippocampus - metabolism; Imatinib Mesylate; Male; Maze Learning - drug effects; Mice; Mice, Transgenic; Nuclear Proteins - metabolism; p73; Phosphorylation - drug effects; Piperazines; Proto-Oncogene Proteins c-abl - metabolism; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Rats, Sprague-Dawley; Signal Transduction; tau Proteins - metabolism; Tumor Protein p73; Tumor Suppressor Proteins - metabolism
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awn125

There is evidence that amyloid β-protein (Aβ) deposits or Aβ intermediates trigger pathogenic factors in Alzheimer's disease patients. We have previously reported that c-Abl kinase activation involved in cell signalling regulates the neuronal death response to Aβ fibrils (Aβf). In the present study we investigated the therapeutic potential of the selective c-Abl inhibitor STI571 on both the intrahippocampal injection of Aβf and APPsw/PSEN1ΔE9 transgenic mice Alzheimer's disease models. Injection of Aβf induced an increase in the numbers of p73 and c-Abl immunoreactive cells in the hippocampal area near to the lesion. Chronic intraperitoneal administration of STI571 reduced the rat behavioural deficit induced by Aβf, as well as apoptosis and tau phosphorylation. Our in vitro studies suggest that inhibition of the c-Abl/p73 signalling pathway is the mechanism underlying of the effects of STI571 on Aβ-induced apoptosis for the following reasons: (i) Aβf induces p73 phosphorylation, the TAp73 isoform levels increase so as to enhance its proapoptotic function, and all these effects where reduced by STI571; (ii) c-Abl kinase activity is required for neuronal apoptosis and (iii) STI571 prevents the Aβ-induced increase in the expression of apoptotic genes. Furthermore, in the Aβ-injected area there was a huge increase in phosphorylated p73 and a larger number of TAp73-positive cells, with these changes being prevented by STI571 coinjection. Moreover, the intraperitoneal administration of STI571 rescued the cognitive decline in APPsw/PSEN1ΔE9 mice, p73 phosphorylation, tau phosphorylation and caspase-3 activation in neurons around Aβ deposits. Besides, we observed a decrease in the number and size of Aβ deposits in the APPsw/PSEN1ΔE9—STI571-treated mice. These results are consistent with the role of the c-Abl/p73 signalling pathway in Aβ neurodegeneration, and suggest that STI571-like compounds would be effective in therapeutic treatments of Alzheimer disease.