Demuro A, Parker I.
Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate.
J Neurosci. 2013 Feb 27;33(9):3824-33.
PubMed.
This paper by Angelo Demuro and Ian Parker reports very careful examination of Ca2+ signaling effects by intracellular amyloid-β oligomers. They used a Xenopus oocyte model system. In previous studies these authors used a similar approach to evaluate Ca2+ influx mediated by extracellular Aβ oligomers, which make Ca2+-permeable pores in the plasma membranes of cells (1). But some evidence suggested that intracellular Aβ may also play an important role in AD pathology (2). In their studies, Demuro and Parker discover that injection of Aβ42 oligomers (but not monomers) results in Ca2+ responses in Xenopus oocytes. In contrast to extracellular Aβ42 application, these responses were dominated by inositol triphosphate receptor (InsP3R)-mediated Ca2+ release mechanism. The authors suggest that this can be explained by direct stimulation of phospholipase C-mediated InsP3 production by Aβ42 oligomers, but they do not measure InsP3 production in their paper.
It is more likely that these effects are mediated by positive feedback of Ca2+ on the InsP3R (3), such that initial endoplasmic reticulum (ER) Ca2+ release induced by Aβ42 oligomer pores is further enhanced via Ca2+-induced Ca2+ release mechanism that involves activation of InsP3R. It is also possible that initial ER Ca2+ release induced by Aβ42 oligomers stimulated Ca2+-dependent PLC and increased levels of InsP3 in oocytes. In any case, although the exact mechanism of the observed effects remains unclear, these results suggest a clear connection between intraneuronal Aβ42 oligomer accumulation and enhanced Ca2+ release from the ER. Many previous reports indicated that enhanced ER Ca2+ release occurs as a result of familial Alzheimer 's disease mutations in presenilins and resulting ER Ca2+ overload (4). In addition, the current study offers a potentially synergistic mechanism of Ca2+ dysregulation based on further enhancement of ER Ca2+ release that depends on intracellular Aβ accumulation. This is yet more evidence to link amyloid-dependent and Ca2+-dependent pathogenic pathways in AD (5).
References:
Demuro A, Smith M, Parker I.
Single-channel Ca(2+) imaging implicates Aβ1-42 amyloid pores in Alzheimer's disease pathology.
J Cell Biol. 2011 Oct 31;195(3):515-24.
PubMed.
Capetillo-Zarate E, Gracia L, Tampellini D, Gouras GK.
Intraneuronal Aβ accumulation, amyloid plaques, and synapse pathology in Alzheimer's disease.
Neurodegener Dis. 2012;10(1-4):56-9.
PubMed.
Bezprozvanny I, Watras J, Ehrlich BE.
Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum.
Nature. 1991 Jun 27;351(6329):751-4.
PubMed.
Supnet C, Bezprozvanny I.
Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis.
Cell Calcium. 2011 Sep;50(3):303-9.
PubMed.
Bezprozvanny I, Mattson MP.
Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease.
Trends Neurosci. 2008 Sep;31(9):454-63.
PubMed.
Comments
UT Southwestern Medical Center at Dallas
This paper by Angelo Demuro and Ian Parker reports very careful examination of Ca2+ signaling effects by intracellular amyloid-β oligomers. They used a Xenopus oocyte model system. In previous studies these authors used a similar approach to evaluate Ca2+ influx mediated by extracellular Aβ oligomers, which make Ca2+-permeable pores in the plasma membranes of cells (1). But some evidence suggested that intracellular Aβ may also play an important role in AD pathology (2). In their studies, Demuro and Parker discover that injection of Aβ42 oligomers (but not monomers) results in Ca2+ responses in Xenopus oocytes. In contrast to extracellular Aβ42 application, these responses were dominated by inositol triphosphate receptor (InsP3R)-mediated Ca2+ release mechanism. The authors suggest that this can be explained by direct stimulation of phospholipase C-mediated InsP3 production by Aβ42 oligomers, but they do not measure InsP3 production in their paper.
It is more likely that these effects are mediated by positive feedback of Ca2+ on the InsP3R (3), such that initial endoplasmic reticulum (ER) Ca2+ release induced by Aβ42 oligomer pores is further enhanced via Ca2+-induced Ca2+ release mechanism that involves activation of InsP3R. It is also possible that initial ER Ca2+ release induced by Aβ42 oligomers stimulated Ca2+-dependent PLC and increased levels of InsP3 in oocytes. In any case, although the exact mechanism of the observed effects remains unclear, these results suggest a clear connection between intraneuronal Aβ42 oligomer accumulation and enhanced Ca2+ release from the ER. Many previous reports indicated that enhanced ER Ca2+ release occurs as a result of familial Alzheimer 's disease mutations in presenilins and resulting ER Ca2+ overload (4). In addition, the current study offers a potentially synergistic mechanism of Ca2+ dysregulation based on further enhancement of ER Ca2+ release that depends on intracellular Aβ accumulation. This is yet more evidence to link amyloid-dependent and Ca2+-dependent pathogenic pathways in AD (5).
References:
Demuro A, Smith M, Parker I. Single-channel Ca(2+) imaging implicates Aβ1-42 amyloid pores in Alzheimer's disease pathology. J Cell Biol. 2011 Oct 31;195(3):515-24. PubMed.
Capetillo-Zarate E, Gracia L, Tampellini D, Gouras GK. Intraneuronal Aβ accumulation, amyloid plaques, and synapse pathology in Alzheimer's disease. Neurodegener Dis. 2012;10(1-4):56-9. PubMed.
Bezprozvanny I, Watras J, Ehrlich BE. Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature. 1991 Jun 27;351(6329):751-4. PubMed.
Supnet C, Bezprozvanny I. Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis. Cell Calcium. 2011 Sep;50(3):303-9. PubMed.
Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 2008 Sep;31(9):454-63. PubMed.
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