Browsing by Author "Chandia-Cristi, America"

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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 Is Required for BDNF-Induced Dendritic Branching and Growth
    (2023) Chandia-Cristi, America; Stuardo, Nicolas; Trejos, Cristian; Leal, Nancy; Urrutia, Daniela; Bronfman, Francisca C.; Rojas, Alejandra Alvarez
    Brain-derived neurotrophic factor (BDNF) induces activation of the TrkB receptor and several downstream pathways (MAPK, PI3K, PLC-gamma), leading to neuronal survival, growth, and plasticity. It has been well established that TrkB signaling regulation is required for neurite formation and dendritic arborization, but the specific mechanism is not fully understood. The non-receptor tyrosine kinase c-Abl is a possible candidate regulator of this process, as it has been implicated in tyrosine kinase receptors' signaling and trafficking, as well as regulation of neuronal morphogenesis. To assess the role of c-Abl in BDNF-induced dendritic arborization, wild-type and c-Abl-KO neurons were stimulated with BDNF, and diverse strategies were employed to probe the function of c-Abl, including the use of pharmacological inhibitors, an allosteric c-Abl activator, and shRNA to downregulates c-Abl expression. Surprisingly, BDNF promoted c-Abl activation and interaction with TrkB receptors. Furthermore, pharmacological c-Abl inhibition and genetic ablation abolished BDNF-induced dendritic arborization and increased the availability of TrkB in the cell membrane. Interestingly, inhibition or genetic ablation of c-Abl had no effect on the classic TrkB downstream pathways. Together, our results suggest that BDNF/TrkB-dependent c-Abl activation is a novel and essential mechanism in TrkB signaling.