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STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's beta-amyloid deposits. | LitMetric

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

Brain

Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Published: September 2008

AI Article Synopsis

  • The study examines the role of c-Abl kinase in Alzheimer's disease and its interaction with amyloid beta-protein (Abeta), proposing that c-Abl may trigger neuronal death. * Researchers tested the effects of STI571, a selective c-Abl inhibitor, in animal models of Alzheimer's, finding it reduced behavioral deficits, apoptosis, and tau phosphorylation caused by Abeta deposits. * Results suggest that STI571 works by inhibiting the c-Abl/p73 signaling pathway, leading to decreased neurodegeneration and cognitive decline, as well as reducing the size of Abeta deposits in brain tissue.

Article Abstract

There is evidence that amyloid beta-protein (Abeta) deposits or Abeta 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 Abeta fibrils (Abeta(f)). In the present study we investigated the therapeutic potential of the selective c-Abl inhibitor STI571 on both the intrahippocampal injection of Abeta(f) and APPsw/PSEN1DeltaE9 transgenic mice Alzheimer's disease models. Injection of Abeta(f) 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 Abeta(f), 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 Abeta-induced apoptosis for the following reasons: (i) Abeta(f) 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 Abeta-induced increase in the expression of apoptotic genes. Furthermore, in the Abeta-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/PSEN1DeltaE9 mice, p73 phosphorylation, tau phosphorylation and caspase-3 activation in neurons around Abeta deposits. Besides, we observed a decrease in the number and size of Abeta deposits in the APPsw/PSEN1DeltaE9-STI571-treated mice. These results are consistent with the role of the c-Abl/p73 signalling pathway in Abeta neurodegeneration, and suggest that STI571-like compounds would be effective in therapeutic treatments of Alzheimer disease.

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Source
http://dx.doi.org/10.1093/brain/awn125DOI Listing

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