Browsing by Author "Gutierrez, Daniela A."

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    Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation
    (2022) Picon-Pages, Pol; Fanlo-Ucar, Hugo; Herrera-Fernandez, Victor; Auselle-Bosch, Sira; Galera-Lopez, Lorena; Gutierrez, Daniela A.; Ozaita, Andres; Alvarez, Alejandra R.; Oliva, Baldomero; Munoz, Francisco J.
    Alzheimer's disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (A beta) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKII alpha and the nuclear translocation of the transcription factor CREB. It is known that A beta oligomers (oA beta) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oA beta on CaMKII alpha. We found that oA beta produce reactive oxygen species (ROS), that induce CaMKII alpha oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKII alpha is active independently of the binding to calcium/calmodulin, and that CaMKII alpha phosphorylation is mutually exclusive with CaMKII alpha oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKII alpha. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKII alpha induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKII alpha oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oA beta.
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    c-Abl Deficiency Provides Synaptic Resiliency Against Aβ-Oligomers
    (2019) Gutierrez, Daniela A.; Vargas, Lina M.; Chandia-Cristi, America; de la Fuente, Catalina; Leal, Nancy; Alvarez, Alejandra R.
    Spine pathology has been implicated in the early onset of Alzheimer & x2019;s disease (AD), where A & x3b2;-Oligomers (A & x3b2;Os) cause synaptic dysfunction and loss. Previously, we described that pharmacological inhibition of c-Abl prevents A & x3b2;Os-induced synaptic alterations. Hence, this kinase seems to be a key element in AD progression. Here, we studied the role of c-Abl on dendritic spine morphological changes induced by A & x3b2;Os using c-Abl null neurons (c-Abl-KO). First, we characterized the effect of c-Abl deficiency on dendritic spine density and found that its absence increases dendritic spine density. While A & x3b2;Os-treatment reduces the spine number in both wild-type (WT) and c-Abl-KO neurons, A & x3b2;Os-driven spine density loss was not affected by c-Abl. We then characterized A & x3b2;Os-induced morphological changes in dendritic spines of c-Abl-KO neurons. A & x3b2;Os induced a decrease in the number of mushroom spines in c-Abl-KO neurons while preserving the populations of immature stubby, thin, and filopodia spines. Furthermore, synaptic contacts evaluated by PSD95/Piccolo clustering and cell viability were preserved in A & x3b2;Os-exposed c-Abl-KO neurons. In conclusion, our results indicate that in the presence of A & x3b2;Os c-Abl participates in synaptic contact removal, increasing susceptibility to A & x3b2;Os damage. Its deficiency increases the immature spine population reducing A & x3b2;Os-induced synapse elimination. Therefore, c-Abl signaling could be a relevant actor in the early stages of AD.
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    c-Abl tyrosine kinase down-regulation as target for memory improvement in Alzheimer's disease
    (2023) Leon, Rilda; Gutierrez, Daniela A.; Pinto, Claudio; Morales Acevedo, Cristián Gonzalo; de la Fuente, Catalina; Riquelme, Cristobal; Cortés Castro, Bastián Ignacio; Gonzalez-Martin, Adrian; Chamorro, David; Espinosa, Nelson; Fuentealba Durand, Pablo José; Cancino Lobos, Gonzalo; Zanlungo Matsuhiro, Silvana; Dulcey, Andres E.; Marugan, Juan J.; Rojas, Alejandra Alvarez
    BackgroundGrowing evidence suggests that the non-receptor tyrosine kinase, c-Abl, plays a significant role in the pathogenesis of Alzheimer's disease (AD). Here, we analyzed the effect of c-Abl on the cognitive performance decline of APPSwe/PSEN1 & UDelta;E9 (APP/PS1) mouse model for AD. MethodsWe used the conditional genetic ablation of c-Abl in the brain (c-Abl-KO) and pharmacological treatment with neurotinib, a novel allosteric c-Abl inhibitor with high brain penetrance, imbued in rodent's chow. ResultsWe found that APP/PS1/c-Abl-KO mice and APP/PS1 neurotinib-fed mice had improved performance in hippocampus-dependent tasks. In the object location and Barnes-maze tests, they recognized the displaced object and learned the location of the escape hole faster than APP/PS1 mice. Also, APP/PS1 neurotinib-fed mice required fewer trials to reach the learning criterion in the memory flexibility test. Accordingly, c-Abl absence and inhibition caused fewer amyloid plaques, reduced astrogliosis, and preserved neurons in the hippocampus. DiscussionOur results further validate c-Abl as a target for AD, and the neurotinib, a novel c-Abl inhibitor, as a suitable preclinical candidate for AD therapies.