c-Abl tyrosine kinase down-regulation as target for memory improvement in Alzheimer’s disease
Rilda León, Daniela Gutiérrez, Claudio Pinto, Cristián Morales, Catalina de la Fuente, Cristóbal Riquelme, Bastián I. Cortés, Adrián González-Martín, David Chamorro, Nelson Espinosa, Pablo Fuentealba, Gonzalo I. Cancino, Silvana Zanlungo, Andrés E. Dulcey, Juan Marugán, Alejandra Álvarez Rojas
Abstract
Background: Growing 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/PSEN1ΔE9 (APP/PS1) mouse model for AD. Methods: We 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. Results: We 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. Discussion: Our 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.