Disorders of the Nervous System
Author: Maximiliano Gabriel Melano | Email: mmelano@immf.uncor.edu
Maximiliano Gabriel Melano1°, Lorena Paola Neila1°,Clara Inés Chungara1°, Emiliano Lautaro Gomez Quintero2°, Gonzalo Quassollo1°, Mariano Bisbal1°
1° Laboratorio de Neurobiología Celular y Molecular, Instituto Ferreyra (INIMEC-CONICET-UNC)
2° Laboratorio de Toxicologia Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas. (UNR-CONICET)
Oligomers of β-amyloid (Aβ) are implicated in dendritic spine and synaptic plasticity alterations associated with Alzheimer’s disease (AD), but the molecular mechanisms remain incompletely understood. In this context, Rho GTPases are crucial for actin dynamics and dendritic spine structure. Most studies examining these proteins in AD utilize classical biochemical techniques that do not allow resolving the spatiotemporal activation dynamics. Recently, a large number of FRET sensors have been refined, enabling radiometric measurements with high spatial and temporal precision. Using this tool, we aimed to obtain new and detailed evidence of the activation dynamics of Rho GTPases during early exposure to pathogenic forms of Aβ1-42 in neuronal cultures. We observed that early exposure to Aβ oligomers causes an increase in RhoA activity after 5 minutes, primarily localized in dendritic spines. After 30 minutes of exposure, RhoA activity decreases and Cdc42 activation rises with a slight increase also localized in dendritic spines. This situation reverses for both GTPases after one hour . Regarding Rac1 activity, our results indicate an increase in dendrites shafts after 5 minutes of exposure. This suggests that changes in Rho GTPase activity related to cytotoxic Aβ exposure correspond to complex activation/inactivation patterns, which highlights the need to investigate more precisely these signaling pathways that could explain the onset of dendritic spine loss in this disease.