Tatiana Adasme, Chile
Universidad Bernardo O´Higgins CIBQAAuthor Of 1 Presentation
AMYLOID-Β OLIGOMERS CONTRIBUTE TO THE CALCIUM DYSFUNCTION IN ALZHEIMER´S DISEASE BY INTERRUPTING NEUROPROTECTIVE GENE EXPRESSION INDUCED BY NEURONAL ACTIVITY
Abstract
Aims
Amyloid-beta oligomers (AβOs) are synaptotoxins that induce aberrant Ca2+-signals and promote ROS generation, leading to synaptic plasticity disruption. We have reported that AβOs induce a sustained but low-intensity cytoplasmic [Ca2+]i increase in neurons, which arises from NMDA receptor-mediated Ca2+ entry and subsequent amplification via Ca2+-induced Ca2+-release, mediated by ryanodine receptor (RyR) channels. We also reported that RyR2 isoform has a key role in the mitochondrial dysfunctions induced by AβOs-treatment in neurons, and in the memory-defects observed in rats injected with AβOs. Since gene expression changes are mediated by the rapid activation and expression of transcription factors, we evaluated the expression of RyR2 and distinct activity-dependent genes regulating the expression of neurotrophic factors and antioxidant enzymes in response to AβOs. We also tested the combined effects of AβOs and Gabazine (GBZ), a GABA(A)-receptor blocker that functions as an inductor of synaptic activity.
Methods
Primary hippocampal cultures were pre-incubated for 6 h with AβOs before the Gabazine (GBZ) stimulation for 2h. RyR2, Npas4, BDNF, Glutamate-Cysteine-Ligase (GCL) and NADPH-Quinone-Oxidoreductase (Nqo1) mRNA expression levels were determined by RT-qPCR.
Results
GBZ alone induced in just 2 h an increase in RyR2 expression, BDNF, Npas4, glutamate-Cysteine-Ligase (GCL), and NADPH-Quinone-Oxidoreductase (Nqo1). Conversely, pre-treatment with AβOs prevented these increases in the mRNA expression levels of these proteins induced by GBZ.
Conclusions
We propose that AβOs block the activation of signaling pathways induced by stimulation of neuronal activity by GBZ, leading to a disruption of the neuroprotective gene expression pathways essential to memory and learning processes, which are affected in neurodegenerative diseases.