Browsing by Author "Alvarez, Alejandra R."

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    Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease
    (WILEY, 2008) Alvarez, Alejandra R.; Klein, Andres; Castro, Juan; Cancino, Gonzalo I.; Amigo, Julio; Mosqueira, Matias; Vargas, Lina M.; Yevenes, L. Fernanda; Bronfman, Francisca C.; Zanlungo, Silvana
    Niemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingo-lipids in the endosomal-lysosomal system. Patients with NPC disease have markedly progressive neuronal loss, mainly of cerebellar Purkinje neurons. There is strong evidence indicating that cholesterol accumulation and trafficking defects activate apoptosis in NPC brains. The purpose of this study was to analyze the relevance of apoptosis and particularly the proapoptotic c-Abl/p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c-Abl/p73 expression and activation in the cerebellum and the effect of therapy with the c-Abl-specific inhibitor imatinib. The proapoptotic c-Abl/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c-Abl with imatinib preserved Purkinje neurons and reduced general cell apoptosis in the cerebellum, improved neurological symptoms, and increased the survival of NPC mice. Moreover, this prosurvival effect correlated with reduced mRNA levels of p73 proapoptotic target genes. Our results suggest that the c-Abl/p73 pathway is involved in NPC neurodegeneration and show that treatment with c-Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.
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    In vivo micro computed tomography detection and decrease in amyloid load by using multifunctionalized gold nanorods: a neurotheranostic platform for Alzheimer's disease
    (Royal Soc Chemistry, 2021) Morales Zavala, Francisco; Jara Guajardo, Pedro; Chamorro Veloso, David Daniel; Riveros, Ana L.; Chandia Cristi, América Valeska; Salgado Cortés, Nicole Andrea; Pismante, Paola; Giralt, Ernest; Sanchez Navarro, Macarena; Araya, Eyleen; Vasquez, Rodrigo; Acosta, Gerardo; Albericio, Fernando; Alvarez, Alejandra R.; Kogan, Marcelo J.
    The development and use of nanosystems is an emerging strategy for the diagnosis and treatment of a broad number of diseases, such as Alzheimer's disease (AD). Here, we developed a neurotheranostic nanosystem based on gold nanorods (GNRs) that works as a therapeutic peptide delivery system and can be detected in vivo for microcomputed tomography (micro-CT), being a diagnostic tool. GNRs functionalized with the peptides Ang2 (a shuttle to the Central Nervous System) and D1 (that binds to the A beta peptide, also inhibiting its aggregation) allowed detecting differences in vivo between wild type and AD mice (APPswe/PSEN1dE9) 15 minutes after a single dose by micro-CT. Moreover, after a recurrent treatment for one month with GNRs-D1/Ang2, we observed a diminution of amyloid load and inflammatory markers in the brain. Thus, this new designed nanosystem exhibits promising properties for neurotheranostics of AD.
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    STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's beta-amyloid deposits
    (OXFORD UNIV PRESS, 2008) Cancino, Gonzalo I.; Toledo, Enrique M.; Leal, Nancy R.; Hernandez, Diego E.; Yevenes, L. Fernanda; Inestrosa, Nibaldo C.; Alvarez, Alejandra R.
    There 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.
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    Synaptic Clustering of PSD-95 Is Regulated by c-Abl through Tyrosine Phosphorylation
    (SOC NEUROSCIENCE, 2010) Perez de Arce, Karen; Varela Nallar, Lorena; Farias, Olivia; Cifuentes, Alejandra; Bull, Paulina; Couch, Brian A.; Koleske, Anthony J.; Inestrosa, Nibaldo C.; Alvarez, Alejandra R.
    The c-Abl tyrosine kinase is present in mouse brain synapses, but its precise synaptic function is unknown. We found that c-Abl levels in the rat hippocampus increase postnatally, with expression peaking at the first postnatal week. In 14 d in vitro hippocampal neuron cultures, c-Abl localizes primarily to the postsynaptic compartment, in which it colocalizes with the postsynaptic scaffold protein postsynaptic density protein-95 (PSD-95) in apposition to presynaptic markers. c-Abl associates with PSD-95, and chemical or genetic inhibition of c-Abl kinase activity reduces PSD-95 tyrosine phosphorylation, leading to reduced PSD-95 clustering and reduced synapses in treated neurons. c-Abl can phosphorylate PSD-95 on tyrosine 533, and mutation of this residue reduces the ability of PSD-95 to cluster at postsynaptic sites. Our results indicate that c-Abl regulates synapse formation by mediating tyrosine phosphorylation and clustering of PSD-95.