Investigating the effects of the jasmonate compounds on Aβ42-induced cell death, oxidative stress, DNA double-strand breaks and synapsin I protein depletion

Introduction: Intracellular accumulation of Amyloid-ß 42 (Aß42) is linked to various neuronal toxicities found in the brains of Alzheimer’s disease (AD) patients. This includes dysregulatory effects on glutamatergic neurotransmission which may contribute to synaptic loss and the inhibition of synaptic plasticity. Moreover, Aß42 promotes oxidative stress, which encourages mitochondrial dysfunction, DNA damage and pro-apoptotic signalling, and has also been linked to synaptic dysfunctions. This is supported by studies reporting protective effects of many exogenous antioxidants against Aß42-dependent neurotoxicity in neurons and on pathological effects including cognitive deficits in AD animal models.
Aims: With the aim of identifying additional antioxidants compounds that minimise the toxic effects of Aß42, we used SH-SY5Y cells and rat hippocampal neuronal cultures to assess the impacts of the jasmonate compounds: 12-oxophytodienoic acid (OPDA), jasmonic acid (JA) and methyl jasmonate (MeJa), in comparison to α-tocopherol (α-T), a well characterised antioxidant, on Aß42-dependent cell death, oxidative stress, DNA damage and Synapsin I protein depletion.
Results: Our results show that Aß42 but not the inactive Aß42-1 reverse peptide, induced significant increases in cell death, which was minimised by α-T and the jasmonate compounds. We also demonstrate that like α-T, the jasmonates exert antioxidant properties and prevent Aß42-dependent increases in ROS. However, in contrast to α-T, we show that the antioxidant effects of the jasmonates are not attributable to free radical scavenging abilities. Moreover, we demonstrate that Aß42-dependent DNA double-strand breaks (DSBs) contribute to synapsin I protein depletion, and that α-T and OPDA opposed the Aß42-mediated synapsin I depletion.
Conclusion: Our findings suggest that the jasmonates provide cytoprotective properties against Aß42-induced neurotoxicity and therefore may have therapeutic benefits in AD. Moreover, our data also suggests that there is a potential link between Aß42-induced synapsin I depletion and DSBs.