Browsing by Author "Álvarez Rojas, Alejandra Beatriz"

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    c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice
    (2011) Cancino Lobos, Gonzalo; Pérez De Arce Guzmán, Karen Andrea; Castro Uribe, Paula Andrea; Toledo Maldonado, Enrique Daniel; Von Bernhardi Montgomery, Rommy Edth B.; Álvarez Rojas, Alejandra Beatriz
    The c-Abl tyrosine kinase is an important link in signal transduction pathways that promote cytoskeletal rearrangement and apoptotic signalling. We have previously shown that amyloid-beta-peptide (A beta) activates c-Abl. Herein we show that c-Abl participates in A beta-induced tau phosphorylation through Cdk5 activation. We found that intraperitoneal administration of STI571, a specific inhibitor for c-Abl kinase, decreased tau phosphorylation in the APPswe/PSEN1 Delta E9 transgenic mouse brain. In addition, when neurons were treated with A beta we observed: (i) an increase in active c-Abl and tau phosphorylation, (ii) the prevention of tau phosphorylation by STI571 and (iii) the inhibition of c-Abl expression by shRNA, as well as the expression of a c-Abl kinase death mutant, decreased AT8 and PHF1 signals. Furthermore, the increase of c-Abl was associated with Tyr15 phosphorylation of Cdk5 and its association with c-Abl. Brains from APPswe/PSEN1 Delta E9 mice showed higher levels of c-Abl and phospho-Cdk5 than wild-type mice. Moreover, STI571 treatment decreased the phospho-Cdk5 levels. Together, the evidence suggests that activation of c-Abl by A beta promotes tau phosphorylation through Tyr15 phosphorylation-mediated Cdk5 activation. (C) 2009 Elsevier Inc. All rights reserved.
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    Lack of Activation of the Unfolded Protein Response in Mouse and Cellular Models of Niemann-Pick Type C Disease
    (2011) Klein Posternack, Andrés David; Mosqueira Montero, Matías José; Martínez, Gabriela; Robledo Plaza, Fermín Alberto; González Bustos, Marcela Paz; Caballero, Benjamín; Cancino Lobos, Gonzalo; Álvarez Rojas, Alejandra Beatriz; Hetz, Claudio; Zanlungo Matsuhiro, Silvana
    Background: Niemann-Pick type C (NPC) disease is a fatal lysosomal storage disease related to progressive neurode-generation secondary to abnormal intracellular accumulation of cholesterol. Signs of endoplasmic reticulum (ER) stress have been reported in other lipidoses. Adaptation to ER stress is mediated by the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates stress or triggers apoptosis of irreversibly damaged cells. Objective: To investigate the possible engagement of ER stress responses in NPC models. Methods: We used NPC1 deficient mice and an NPC cell-based model by knocking down the expression of NPC1 to measure several UPR markers through different approaches. Results: Despite expectations that the UPR will be activated in NPC, our results indicate a lack of ER stress reactions in the cerebellum of symptomatic mice. Similarly, knocking down NPC1 in Neuro2a cells leads to clear cholesterol accumulation without evidence of UPR activation. Conclusion: Our results suggest that cholesterol overload and neuronal dysfunction in NPC is not associated with ER stress, which contrasts with recent reports suggesting the activation of the UPR in other lysosomal storage diseases. Copyright (c) 2010 S. Karger AG, Basel