Supnet C, Grant J, Kong H, Westaway D, Mayne M.
Amyloid-beta-(1-42) increases ryanodine receptor-3 expression and function in neurons of TgCRND8 mice.
J Biol Chem. 2006 Dec 15;281(50):38440-7.
Please login to recommend the paper.
To make a comment you must login or register.
This paper by Supnet et al. aimed to investigate the role of RyR-3 on Aβ1-42-mediated changes in intracellular Ca2+ homeostasis. This interesting study demonstrated that Aβ1-42-mediated alterations in intracellular Ca2+ homeostasis are regulated, in part, through a direct increase of RyR-3 expression and function. In cortical neurons from C57B16 mice treated with extracellular Aβ, the Aβ1-42 isoform was shown to specifically increase RyR-3 gene expression. Similar results were observed in cortical neurons obtained from a mouse model of AD, the (Tg)CRND8 mice, which produces endogenous Aβ1-42, and also in brain tissue from 4- to 4.5-month-old Tg animals. Moreover, increased RyR-3 protein levels were detected in both neuronal cultures and brain tissue from Tg mice. Furthermore, the increased RyR-3 mRNA and protein were shown to be implicated in the higher levels of Ca2+ observed in neurons from (Tg)CRND8 mice. These results are in line with previously published results from several independent laboratories suggesting the involvement of ER Ca2+ channels in Aβ-induced cell death and help to elucidate the mechanisms involved in ER dysfunction in AD, an early event implicated in the pathogenesis of this neurodegenerative disorder.
This paper opens new avenues of AD research, which might lead to the identification of novel therapeutic targets. It would be helpful to elucidate which Aβ1-42 species, oligomers or fibrils, are responsible for the alterations in RyR-3 expression and function. In addition, it is important to analyze the temporal correlation between RyR-3 changes and increased soluble Aβ levels and Aβ plaque formation. Furthermore, it would be interesting to investigate the role of increased RyR-3 expression and function on behavioral disturbances, using siRNA to determine if cognitive deficits in (Tg)CRND8 mice are ameliorated. Finally, it seems urgent to evaluate what is the impact of RyR-3 alterations in synaptic and neuronal loss, determining whether these Aβ1-42-mediated alterations in intracellular Ca2+ homeostasis, regulated through a direct increase of RyR-3 expression and function, lead to synaptic dysfunction and activation of cell death pathways.