036 | Exposure to β-amyloid oligomers promotes spatiotemporal patterns of activation in Rho GTPas; Rac1, Cdc42 and RhoA.

Cellular and Molecular Neurobiology

Author: Maximiliano Gabriel Melano | Email: mmelano@immf.uncor.edu

Maximiliano Gabriel Melano , Lorena Neila , Mariano Bisbal

1° Laboratorio de Neurobiología Celular y Molecular, Instituto de Investigación Mercedes y Martín Ferreyra ( INMEC-CONICET-UNC), Córdoba, Argentina.

Synaptic loss is a key factor in cognitive dysfunction associated with Alzheimer’s disease (AD). Oligomers of β-amyloid (Aβ) are implicated in dendritic spine alteration and synaptic plasticity, but the molecular mechanisms remain incompletely understood. In this context, Rho GTPases, functioning as molecular switches, are crucial for actin dynamics and dendritic spine structure. In most studies examining their activation in AD, biochemical extraction assays, constitutively active or negative dominant mutants are used, which fail to resolve spatio-temporal activation dynamics. Recently, Förster resonance energy transfer (FRET) sensors have been developed and refined, enabling highly precise spatial and temporal radiometric measurements. Using these tools, we aimed to gather new and detailed evidence on the activation dynamics of Rho GTPases—RhoA, Rac1, and Cdc42—during early and late exposure to pathogenic forms of β-amyloid 1-42 in cell lines and neuronal cultures. Early exposure to Aβ1-42 oligomers led to increased Rac1 activity and reduced RhoA at 30 minutes, which reversed after an hour, with RhoA increasing and Cdc42 decreasing. After 24 hours of exposure, Rac1 and Cdc42 activity declined, while RhoA remained unchanged. These findings suggest that changes in Rho GTPase activity, linked to AD, are more complex than previously thought, underscoring the need for further investigation into signaling pathways governing the onset of dendritic spine loss.