Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers*♦

By A. Demuro, E. Mina, R. Kayed, S. Milton, I. Parker, C. Glabe. Journal of Biological Chemistry, 2005

1,034 citations recorded by the source corpus.

Increasing evidence suggests that amyloid peptides associated with a variety of degenerative diseases induce neurotoxicity in their intermediate oligomeric state, rather than as monomers or fibrils. To test this hypothesis and investigate the possible involvement of Ca2+ signaling disruptions in amyloid-induced cytotoxicity, we made homogeneous preparations of disease-related amyloids (Aβ, prion, islet amyloid polypeptide, polyglutamine, and lysozyme) in various aggregation states and tested their actions on fluo-3-loaded SH-SY5Y cells. Application of oligomeric forms of all amyloids tested (0.6–6 μgml–1) rapidly (∼5 s) elevated intracellular Ca2+, whereas equivalent amounts of monomers and fibrils did not. Ca2+ signals evoked by Aβ42 oligomers persisted after depletion of intracellular Ca2+ stores, and small signals remained in Ca2+-free medium, indicating contributions from both extracellular and intracellular Ca2+ sources. The increased membrane permeability to Ca2+ cannot be attributed to activation of endogenous Ca2+ channels, because responses were unaffected by the potent Ca2+-channel blocker cobalt (20 μm). Instead, observations that Aβ42 and other oligomers caused rapid cellular leakage of anionic fluorescent dyes point to a generalized increase in membrane permeability. The resulting unregulated flux of ions and molecules may provide a common mechanism for oligomer-mediated toxicity in many amyloidogenic diseases, with dysregulation of Ca2+ ions playing a crucial role because of their strong trans-membrane concentration gradient and involvement in cell dysfunction and death.

Subfields: Molecular Biology, Physiology, Plant Science

View Paper: https://www.semanticscholar.org/paper/976d61026b9b8ce272378f880f1ac2106bd44307

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In Molecular Biology

1. D. Selkoe
2. L. Mucke
3. G. Shankar
4. D. Walsh
5. Ehud Gazit
6. David Watson
7. William F. DeGrado
8. I. Korendovych

In Physiology

1. D. Selkoe
2. L. Mucke
3. G. Shankar
4. D. Walsh
5. Nina E. Shepardson
6. Shaomin Li
7. Chunyan Guo
8. J. Kong

Citations in the corpus

• Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding (2007, background): “…have been suggested to underlie the increase in intracellular calcium induced by amyloidogenic proteins: increase in membrane permeability (Demuro et al., 2005), insertion into the membrane and formation of a pore (Kawahara et al., 2000; Arispe, 2004; Lashuel and Lansbury, 2006), and a…”
• Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. (2012, background): “Numerous studies using high levels of synthetic Ab40 or Ab42 indicate that such preparations can bind to membranes and perturb their structure, in some cases causing actual holes in the membrane that could conduct ions and thus induce cytotoxicity (Demuro et al. 2005; Lin et al. 2001).”
• Soluble oligomers of amyloid β-protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake (2009, positive): “To assess whether intracellular calcium stores also regulate Aβ-mediated LTD, as they have been reported to do for Aβ neurotoxicity (Demuro et al., 2005), we tested two compounds that inhibit the release of intracellular Ca2+ stores, ryanodine and U73122.”
• Aβ plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks (2008, neutral): “Existing evidence has shown that exogenous application of synthetic amyloid-beta or oligomeric aggregates leads to a rapid, and sustained rise in [Ca]i in cultured cells (Demuro et al., 2005; Guo et al., 1999b; Mattson et al., 1993; Mattson et al., 1992).”
• ER stress and neurodegenerative diseases (2006, background): “These can impair various signaling and synaptic functions of the neuron by influencing intracellular calcium levels and cellular membranes.(26,43) The role of ER in these processes remain to be studied in more detail.”
• Inhibition of Amyloid Fibril Formation by Polyphenols: Structural Similarity and Aromatic Interactions as a Common Inhibition Mechanism (2006, background): “The suggested direct effects are: (a) pore formation in cellular membranes (35,36); (b) permeation effect of amyloidogenic bundles, which lead to membranal instability (37,38).”
• Oxidative stress in neurodegenerative diseases (2012, background): “Thus, any disruption of calcium homeostasis may disrupt the cellular physiology [16] .”
• Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options (2009, background): “Thus, any disturbance in stimulus and regulation of calcium pathway may disrupt the cellular physiology [1].”
• Aβ Oligomers – a decade of discovery (2007, background): “…and colleagues examined the effect of three distinct assembly forms of synthetic Ab – high molecular weight oligomers (formed as described by Demuro et al. 2005), ADDLs and fibrillar Ab – they found that all three preparations were toxic to primary human cortical neurons, but that the…”
• Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. (2012, neutral): “Such oligomers increase cytosolic free Ca2+ (112), which is known to inhibit insulin-induced hippocampal IR pY (113).”