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

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dc.contributor.authorCancino, Gonzalo I.
dc.contributor.authorToledo, Enrique M.
dc.contributor.authorLeal, Nancy R.
dc.contributor.authorHernandez, Diego E.
dc.contributor.authorYevenes, L. Fernanda
dc.contributor.authorInestrosa, Nibaldo C.
dc.contributor.authorAlvarez, Alejandra R.
dc.date.accessioned2024-01-10T12:08:49Z
dc.date.available2024-01-10T12:08:49Z
dc.date.issued2008
dc.description.abstractThere is evidence that amyloid beta-protein (A beta) deposits or A intermediates trigger pathogenic factors in Alzheimers disease patients. We have previously reported that c-Abl kinase activation involved in cell signalling regulates the neuronal death response to A fibrils (A beta(f)). In the present study we investigated the therapeutic potential of the selective c-Abl inhibitor STI57I on both the intrahippocampal injection of Af and APPsw/PSENI Delta E9 transgenic mice Alzheimers disease models. Injection of A beta(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 A beta(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 A beta-induced apoptosis for the following reasons: (i) A beta(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 A beta-induced increase in the expression of apoptotic genes. Furthermore, in the A-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/PSENI Delta E9 mice, p73 phosphorylation, tau phosphorylation and caspase-3 activation in neurons around A beta deposits. Besides, we observed a decrease in the number and size of A beta deposits in the APPsw/PSENI Delta E9-STI571-treated mice. These results are consistent with the role of the c-Abl/p73 signalling pathway in A beta neurodegeneration, and suggest that STI571-like compounds would be effective in therapeutic treatments of Alzheimer disease.
dc.description.funderFONDECYT
dc.description.funderAra Parseghian Medical Research Foundation
dc.fechaingreso.objetodigital2024-04-30
dc.format.extent18 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1093/brain/awn125
dc.identifier.eissn1460-2156
dc.identifier.issn0006-8950
dc.identifier.pubmedidMEDLINE:18559370
dc.identifier.urihttps://doi.org/10.1093/brain/awn125
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/76431
dc.identifier.wosidWOS:000258862200018
dc.information.autorucCiencias Biológicas;Cancino G;S/I;17709
dc.information.autorucCiencias Biológicas;Hernández D;S/I;142368
dc.information.autorucCiencias Biológicas;Inestrosa NC;S/I;99331
dc.information.autorucCiencias Biológicas;Leal N;S/I;10604
dc.information.autorucCiencias Biológicas;Toledo E;S/I;4625
dc.information.autorucCiencias Biológicas;Yévenes F;S/I;142390
dc.information.autorucCiencias Biológicas;Álvarez A;S/I;83681
dc.language.isoen
dc.nota.accesocontenido parcial
dc.pagina.final2442
dc.pagina.inicio2425
dc.publisherOXFORD UNIV PRESS
dc.revistaBRAIN
dc.rightsacceso restringido
dc.subjectAlzheimer's disease
dc.subjectp73
dc.subjectc-Abl
dc.subjectbehavioural impairments
dc.subjectamyloid beta-peptide
dc.subjectABL TYROSINE KINASE
dc.subjectC-ABL
dc.subjectP53 FAMILY
dc.subjectMUTANT PRESENILIN-1
dc.subjectHIPPOCAMPAL-NEURONS
dc.subjectIMATINIB MESYLATE
dc.subjectNERVOUS-SYSTEM
dc.subjectDNA-DAMAGE
dc.subjectCELL-DEATH
dc.subjectP73
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleSTI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's beta-amyloid deposits
dc.typeartículo
dc.volumen131
sipa.codpersvinculados17709
sipa.codpersvinculados142368
sipa.codpersvinculados99331
sipa.codpersvinculados10604
sipa.codpersvinculados4625
sipa.codpersvinculados142390
sipa.codpersvinculados83681
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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