Amyloid-β-(1-42) Increases Ryanodine Receptor-3 Expression and Function in Neurons of TgCRND8 Mice

Abstract

Disruption of intracellular calcium homeostasis precedes the neurodegeneration that occurs in Alzheimer disease (AD).In experiments performed in nominal extracellular calcium, neurons from Tg mice had significant increases in intracellular calcium following ryanodine or glutamate treatment compared with littermate controls, which was abolished by treatment with small interfering RNA directed to RyR-3, indicating that the higher levels of calcium originated from RyR-3-regulated stores. Taken together, these observations suggest that A␤-(1-42)-mediated changes in intracellular calcium homeostasis is regulated in part through a direct increase of RyR-3 expression and function.

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…[51][52][53] An increased expression of the ryanodine receptor (RYR), particularly the RYR3 isoform, 53 is one cause for this hypersensitivity of the internal release mechanism. 52,[54][55][56] The increase in RYR expression results in a greater sensitivity to Ca 2+ elevations during normal synaptic transmission.…”

Endoplasmic Reticulum Ca2+Handling in Excitable Cells in Health and Disease

“…Studies in brain slice preparations have also revealed increased RyRevoked Ca 2ϩ responses across specific neuronal compartments, including the soma and perinuclear regions, and particularly high release in dendrites and spine heads (Stutzmann et al, 2006;Goussakov et al, 2010). In asymptomatic young mice, this was associated with an increase in the RyR2 isoform (Chakroborty et al, 2009), whereas increased RyR3 expression has been observed at later disease stages concurrent with A␤ 1-42 expression (Supnet et al, 2006). Although mutant PS1-expressing mice seem to be cognitively and neurophysiologically normal at this younger, presymptomatic age (Oddo et al, 2003), upon manipulation of the RyR-sensitive stores, it is apparent that these neurons are using a markedly different Ca 2ϩ signaling system to support neurotransmission and plasticity (Chakroborty et al, 2009).…”

“…Concomitant with the impairment in leak channel function, the increase in RyR expression is thought to be a compensatory and neuroprotective response to assume the leak channel role and normalize ER store levels . Other neuroprotective roles of the RyR3 isoform have also been proposed at later disease stages, such that increased RyR3 expression is observed upon A␤ 42 exposure, whereas knockdown of RyR3 increases amyloid pathologic condition (Supnet et al, 2006. Likewise, long-term exposure to RyR blockers increases amyloid pathologic condition and cytotoxicity .…”

“…A␤ 42 peptides have been shown to increase RyR3 expression in transgenic mouse models of AD (Supnet et al, 2006 as well as to increase the RyR open channel probability, resulting in increased Ca 2ϩ flux (Shtifman et al, 2010). Likewise, A␤ peptides increase the IP 3 -evoked Ca 2ϩ response in neurons directly (Schapansky et al, 2007), as well as indirectly through the alteration of G q -coupled mGlurR5 receptors (Casley et al, 2009;Renner et al, 2010).…”

Alteration of Neuron-Glia Interactions in Neurodegeneration: Molecular Biomarkers and Therapeutic Strategy

“…Therefore, expression and functional activity of CD38 in astrocytes and/or neurons, and ectocellular action of cADPR and NAADP + on astrocytes resulting in Ca 2+ signaling (Heidemann et al, 2005;Pawlikowska et al, 1996) would have physiological and pathophysiological meaning as a mechanism of Ca 2+ signaling involved in neuron-astroglia cell interactions. Alterations in ryanodine receptor binding and function are very early events in the pathogenesis of Alzheimer's disease (Kelliher et al, 1999) while A increases ryanodine receptors expression and function in cortical neurons (Supnet et al, 2006). Taking into account importance of neuronal calcium mishandling in the development of Alzheimer's disease (Verkhratsky, et al, 1998), one can suggest involvement of cADPR-associated signaling pathways in observed ryanodine receptor dysfunction.…”