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Calcium Ions Promote Formation of Amyloid β-Peptide (1–40) Oligomers Causally Implicated in Neuronal Toxicity of Alzheimer's Disease

By Anna Itkin, Vincent Dupres, Yves F. Dufrêne, Burkhard Bechinger, Jean-Marie Ruysschaert and Vincent Raussens

Abstract

Amyloid β-peptide (Aβ) is directly linked to Alzheimer's disease (AD). In its monomeric form, Aβ aggregates to produce fibrils and a range of oligomers, the latter being the most neurotoxic. Dysregulation of Ca2+ homeostasis in aging brains and in neurodegenerative disorders plays a crucial role in numerous processes and contributes to cell dysfunction and death. Here we postulated that calcium may enable or accelerate the aggregation of Aβ. We compared the aggregation pattern of Aβ(1–40) and that of Aβ(1–40)E22G, an amyloid peptide carrying the Arctic mutation that causes early onset of the disease. We found that in the presence of Ca2+, Aβ(1–40) preferentially formed oligomers similar to those formed by Aβ(1–40)E22G with or without added Ca2+, whereas in the absence of added Ca2+ the Aβ(1–40) aggregated to form fibrils. Morphological similarities of the oligomers were confirmed by contact mode atomic force microscopy imaging. The distribution of oligomeric and fibrillar species in different samples was detected by gel electrophoresis and Western blot analysis, the results of which were further supported by thioflavin T fluorescence experiments. In the samples without Ca2+, Fourier transform infrared spectroscopy revealed conversion of oligomers from an anti-parallel β-sheet to the parallel β-sheet conformation characteristic of fibrils. Overall, these results led us to conclude that calcium ions stimulate the formation of oligomers of Aβ(1–40), that have been implicated in the pathogenesis of AD

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3065491
Provided by: PubMed Central

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Citations

  1. (1997). A beta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse.
  2. (2002). A[beta](25-35) and A[beta](1-40) act on different calcium channels in CA1 hippocampal neurons.
  3. (2007). A+ | | Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-Daspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine.
  4. (2006). Acceleration of amyloid beta-peptide aggregation by physiological concentrations of calcium.
  5. (1994). Aggregation of Amyloid Beta-Protein and Its Neurotoxicity - Enhancement by Aluminum and Other Metals.
  6. (2007). Altered Calcium Homeostasis in Old Neurons.
  7. (1993). Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum.
  8. (2000). Alzheimer’s b-Amyloid, Human Islet Amylin, and Prion Protein Fragment Evoke Intracellular Free Calcium Elevations by a Common Mechanism in a Hypothalamic GnRH Neuronal Cell Line.
  9. (2001). Alzheimer’s disease: Genes, proteins, and therapy.
  10. (1992). Alzheimers-Disease - the Amyloid Cascade Hypothesis.
  11. (2011). Amyloid b-Peptide Oligomers Stimulate RyR-Mediated Ca 2+ Release Inducing Mitochondrial Fragmentation in Hippocampal Neurons and Prevent RyRMediated Dendritic Spine Remodeling Produced by BDNF.
  12. (2004). Amyloid peptide channels.
  13. (2009). Antiparallel beta-sheet: a signature structure of the oligomeric amyloid betapeptide.
  14. (1992). BetaAmyloid Peptides Destabilize Calcium Homeostasis and Render Human Cortical-Neurons Vulnerable to Excitotoxicity.
  15. (2009). Ca2+, within the physiological concentrations, selectively accelerates
  16. (1994). Calcium and Neuronal Injury in Alzheimer’s Disease.
  17. (2002). Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease.
  18. (2005). Calcium dyspegulation, IP3 signaling, and Alzheimer’s disease.
  19. (2005). Calcium dysregulation in Alzheimer’s disease: Recent advances gained from genetically modified animals.
  20. (2008). Calcium dysregulation in Alzheimer’s disease.
  21. (1994). Calcium Hypothesis of Alzheimer’s Disease and Brain Aging.
  22. (1994). Calcium Ionophore Increases Amyloid-Beta Peptide Production by Cultured-Cells.
  23. (1998). Calcium responses in fibroblasts from asymptomatic members of Alzheimer’s disease families.
  24. (2006). Calcium-mediated transient phosphorylation of tau and amyloid precursor protein followed by intraneuronal amyloid-beta accumulation.
  25. (2007). Conversion of non-fibrillar [beta]-sheet oligomers into amyloid fibrils in Alzheimer’s disease amyloid peptide aggregation.
  26. (2000). Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline.
  27. (2009). Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice.
  28. (1994). Determination of soluble and membrane protein structure by Fourier transform infrared spectroscopy. I. Assignments and model compounds.
  29. (1998). Diffusible, nonfibrillar ligands derived from A beta(1-42) are potent central nervous system neurotoxins.
  30. (1991). Effects of elevated intracellular calcium levels on the cytoskeleton and tau in cultured human cortical neurons.
  31. (2004). Enhancement of NMDA responses by [beta]-amyloid peptides in the hippocampus in vivo.
  32. (1989). Fluorometric-Determination of Amyloid Fibrils Invitro Using the Fluorescent Dye,
  33. (1993). Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1-40)] in bilayer membranes.
  34. (2006). Highresolution atomic force microscopy of soluble A beta 42 oligomers.
  35. (1995). Image-Analysis of Beta-Amyloid Load in Alzheimers-Disease and Relation to Dementia Severity.
  36. (2003). In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis.
  37. (1976). Infrared-Spectra and Resonance Interaction of Amide-One Vibration of Anti-Parallel-Chain Pleated Sheet.
  38. (2007). Intracellular amyloid-beta in Alzheimer’s disease.
  39. (2004). Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide.
  40. (1992). Linkage and Mutational Analysis of Familial Alzheimer-Disease Kindreds for the App Gene Region.
  41. (2008). Linking calcium to A beta and Alzheimer’s disease.
  42. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.
  43. (2002). Medicine - The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics.
  44. (1999). Mitochondria in the life and death of neurons.
  45. (2004). Molecular pathways to neurodegeneration.
  46. (2007). Natural Oligomers of the Alzheimer Amyloid-{beta} Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway.
  47. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal longterm potentiation in vivo.
  48. (2008). Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease.
  49. (2002). Oligomeric and Fibrillar Species of Amyloid-beta Peptides Differentially Affect Neuronal Viability.
  50. (2004). Pathways towards and away from Alzheimer’s disease (vol 430, pg 631,
  51. (2004). Prefibrillar Amyloid Protein Aggregates Share Common Features of Cytotoxicity.
  52. (2005). Small non-fibrillar assemblies of amyloid [beta]-protein bearing the Arctic mutation induce rapid neuritic degeneration.
  53. (1999). Soluble Amyloid {beta} Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease.
  54. (2009). Soluble Oligomers of Amyloid beta Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake.
  55. (2002). Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not longterm depression in rat dentate gyrus.
  56. (1999). Soluble pool of A beta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease.
  57. (2007). Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide.
  58. (2007). Study on the binding of Thioflavin T to beta-sheet-rich and non-beta-sheet cavities.
  59. (2007). Synaptic memory mechanisms: Alzheimer’s disease amyloid beta-peptide-induced dysfunction.
  60. (2001). Targeting small A beta oligomers: the solution to an Alzheimer’s disease conundrum?
  61. (2001). The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced A[beta] protofibril formation.
  62. (2006). The Arctic Alzheimer mutation facilitates early intraneuronal A beta aggregation and senile plaque formation in transgenic mice.
  63. (2005). The binding of thioflavin-T to amyloid fibrils: localisation and implications.
  64. (1991). The Molecular Pathology of Alzheimers-Disease.
  65. (2007). The pathogenesis of alzheimers disease - Is it a lifelong "Calciumopathy"?
  66. Toescu EC (2002) Changes in Mitochondrial Status Associated with Altered Ca2+ Homeostasis in Aged Cerebellar Granule Neurons in Brain Slices.
  67. (1999). Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.
  68. (2004). Westlind-Danielsson A