Browsing by Author "Morales Acevedo, Cristián Gonzalo"

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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.