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Uncovering the Early Events Associated with Oligomeric Aβ-Induced Src Activation.

Authors :
Mota SI
Fão L
Coelho P
Rego AC
Source :
Antioxidants (Basel, Switzerland) [Antioxidants (Basel)] 2023 Sep 16; Vol. 12 (9). Date of Electronic Publication: 2023 Sep 16.
Publication Year :
2023

Abstract

Soluble Aβ <subscript>1-42</subscript> oligomers (AβO) are formed in the early stages of Alzheimer's disease (AD) and were previously shown to trigger enhanced Ca <superscript>2+</superscript> levels and mitochondrial dysfunction via the activation of N -methyl-D-aspartate receptors (NMDAR). Src kinase is a ubiquitous redox-sensitive non-receptor tyrosine kinase involved in the regulation of several cellular processes, which was demonstrated to have a reciprocal interaction towards NMDAR activation. However, little is known about the early-stage mechanisms associated with AβO-induced neurodysfunction involving Src. Thus, in this work, we analysed the influence of brief exposure to oligomeric Aβ <subscript>1-42</subscript> on Src activation and related mechanisms involving mitochondria and redox changes in mature primary rat hippocampal neurons. Data show that brief exposure to AβO induce H <subscript>2</subscript> O <subscript>2</subscript> -dependent Src activation involving different cellular events, including NMDAR activation and mediated intracellular Ca <superscript>2+</superscript> rise, enhanced cytosolic and subsequent mitochondrial H <subscript>2</subscript> O <subscript>2</subscript> levels, accompanied by mild mitochondrial fragmentation. Interestingly, these effects were prevented by Src inhibition, suggesting a feedforward modulation. The current study supports a relevant role for Src kinase activation in promoting the loss of postsynaptic glutamatergic synapse homeostasis involving cytosolic and mitochondrial ROS generation after brief exposure to AβO. Therefore, restoring Src activity can constitute a protective strategy for mitochondria and related hippocampal glutamatergic synapses.

Details

Language :
English
ISSN :
2076-3921
Volume :
12
Issue :
9
Database :
MEDLINE
Journal :
Antioxidants (Basel, Switzerland)
Publication Type :
Academic Journal
Accession number :
37760073
Full Text :
https://doi.org/10.3390/antiox12091770