Article thumbnail

Phosphorylation of amyloid beta (Aβ) peptides – A trigger for formation of toxic aggregates in Alzheimer's disease

By Sathish Kumar and Jochen Walter

Abstract

Alzheimer's disease (AD) is the most common form of dementia and associated with the progressive accumulation of amyloid β-peptides (Aβ) in form of extracellular amyloid plaques in the human brain. A critical role of Aβ in the pathogenesis of AD is strongly supported by gene mutations that cause early-onset familial forms of the disease. Such mutations have been identified in the APP gene itself and in presenilin 1 and 2. Importantly, all the identified mutations commonly lead to early deposition of extracellular plaques likely by increasing the generation and/or aggregation of Aβ. However, such mutations are very rare and molecular mechanisms that might trigger aggregation and deposition of Aβ, in the most common late onset AD are largely unknown. We recently demonstrated that extracellular Aβ undergoes phosphorylation by a cell surface-localized or secreted form of protein kinase A. The phosphorylation of serine residue 8 promotes aggregation by stabilization of β-sheet conformation of Aβ and increased formation of oligomeric Aβ aggregates that represent nuclei for fibrillization. Phosphorylated Aβ was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated Aβ. Together, these findings demonstrate a novel molecular mechanism that triggers aggregation and toxicity of Aβ. Thus, phosphorylation of Aβ could be relevant in the pathogenesis of late onset AD. The identification of extracellular protein kinase A should also stimulate pharmacological approaches to decrease Aβ phosphorylation in the therapy and/or prevention of AD

Topics: Research Perspective
Publisher: Impact Journals LLC
OAI identifier: oai:pubmedcentral.nih.gov:3184981
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage.
  2. A role for cyclooxygenase-1 in betaamyloid-induced neuroinflammation. Aging
  3. A: Conformations and biological activities of amyloid beta peptide 25-35. Curr Protein Pept Sci
  4. (1999). A: Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev
  5. (2011). A: The role of phosphorylation in synucleinopathies: focus on Parkinson's disease. CNS Neurol Disord Drug Targets 2010;9:471-481. www.impactaging.com 10 AGING,
  6. AE: Comparative analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer's disease brains.
  7. (1998). AE: Irreversible dimerization/tetramerization and post-translational modifications inhibit proteolytic degradation of A beta peptides of Alzheimer's disease.
  8. (1997). AE: Isolation, chemical characterization, and quantitation of A beta 3-pyroglutamyl peptide from neuritic plaques and vascular amyloid deposits.
  9. (2011). Alzheimer's disease facts and figures.
  10. Alzheimer's disease: genes, proteins, and therapy.
  11. (1996). Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain.
  12. Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques.
  13. (1992). Amyloid beta-peptide is produced by cultured cells during normal metabolism.
  14. Amyloid plaque core protein in Alzheimer disease and Down syndrome.
  15. ATP- and adenosine-mediated signaling in the central nervous system: the role of extracellular ATP in hippocampal long-term potentiation.
  16. B: Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease.
  17. Barford D: The effects of phosphorylation on the structure and function of proteins.
  18. Barnekow A: Ecto-protein kinase activities in normal and transformed cells.
  19. Berezovska O: Mutations in amyloid precursor protein affect its interactions with presenilin/gammasecretase.
  20. Bosetti F: Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid. Aging
  21. Buee L: Abnormal Tau phosphorylation of the Alzheimer-type also occurs during mitosis.
  22. C: Phosphorylation regulates intracellular trafficking of beta-secretase.
  23. CE: Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
  24. CM: Rationalization of the effects of mutations on peptide and protein aggregation rates.
  25. Concomitant detection of beta-amyloid peptides with N-terminal truncation and different C-terminal endings in cortical plaques from cases with Alzheimer's disease, senile monkeys and triple transgenic mice.
  26. (1995). Cotman CW: Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro.
  27. (1991). Cotman CW: In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity.
  28. DC: Alzheimer's disease: insights from Drosophila melanogaster models.
  29. (1999). De Strooper B: The presenilins in Alzheimer's disease--proteolysis holds the key.
  30. Delacourte A: Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach.
  31. Delanty N: Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease.
  32. DM: Aggregation and catabolism of disease-associated intraAbeta mutations: reduced proteolysis of AbetaA21G by neprilysin.
  33. (1995). Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques.
  34. (2009). E: Mitochondrial superoxide: a key player in Alzheimer's disease. Aging
  35. (1993). el-Moatassim C: Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides.
  36. (1994). Evidence for CKI and CKII at the cell surface.
  37. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.
  38. (1992). Extracellular ATP and cell signalling.
  39. (2011). Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease.
  40. Fahrenholz F: The non-amyloidogenic pathway: structure and function of alpha-secretases.
  41. (2011). Functional activity of the novel Alzheimer's amyloid beta-peptide interacting domain (AbetaID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis. Gene
  42. (1998). Geddes JW: N-terminal heterogeneity of parenchymal and cerebrovascular Abeta deposits.
  43. (1999). Gejyo F: Kinetic analysis of amyloid fibril formation. Methods Enzymol
  44. Gourine VN: Release of ATP in the central nervous system during systemic inflammation: real-time measurement in the hypothalamus of conscious rabbits.
  45. GV: The role of tau phosphorylation and cleavage in neuronal cell death.
  46. GV: The role of tau phosphorylation in the pathogenesis of Alzheimer's disease.
  47. (2002). H: Modeling Alzheimer's disease and other proteopathies in vivo: is seeding the key? Amino Acids
  48. H: Purinergic signalling in the nervous system: an overview.
  49. (1994). H: Racemization of Asp23 residue affects the aggregation properties of Alzheimer amyloid beta protein analogues.
  50. (2011). High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from www.impactaging.com 8 AGING,
  51. HU: Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides.
  52. Hyman BT: Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy.
  53. III: Diversity of Abeta deposits in the aged brain: a window on molecular heterogeneity?
  54. III: The Amyloid Hypothesis and the clearance and degradation of Alzheimer's beta-peptide.
  55. (1996). Induced release of cell surface protein kinase yields CK1- and CK2-like enzymes in tandem.
  56. Iqbal K: Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer's disease.
  57. (1992). Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids.
  58. Isomerization and/or racemization at Asp23 of Abeta42 do not increase its aggregative ability, neurotoxicity, and radical productivity in vitro.
  59. Kranias EG: Phosphorylation of glutathione-S-transferase by protein kinase C-alpha implications for affinity-tag purification.
  60. (1993). Kreizman T: Evidence for an extra-cellular function for protein kinase A. Mol Cell Biochem
  61. L: A physiological role for amyloid-beta protein:enhancement of learning and memory.
  62. L: Signaling effect of amyloid-beta(42) on the processing of AbetaPP.
  63. LaFerla FM: Alzheimer's disease.
  64. Lashuel HA: Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions.
  65. Lashuel HA: Phosphorylation of synucleins by members of the Polo-like kinase family.
  66. (2011). LF: Phosphorylation, subcellular www.impactaging.com 9 AGING,
  67. LI: Abnormal phosphorylation of the microtubuleassociated protein tau (tau) in Alzheimer cytoskeletal pathology.
  68. Lomas DA: Using a Drosophila model of Alzheimer's disease.
  69. (1997). Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem
  70. Modulation of 'A'-type K+ current by rodent and human forms of amyloid beta protein.
  71. Molecular genetics of Alzheimer's disease.
  72. Mucke L: Tau reduction prevents Abetainduced defects in axonal transport.
  73. Nakaya T: Regulation of amyloid beta-protein precursor by phosphorylation and protein interactions.
  74. On the seeding and oligomerization of pGluamyloid peptides (in vitro).
  75. Papadopoulos V: Function of beta-amyloid in cholesterol transport: a lead to neurotoxicity.
  76. Pathways linking Abeta and tau pathologies.
  77. Pedata F: ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia.
  78. Peers C: Physiological roles for amyloid beta peptides.
  79. Phosphorylated amyloid-beta: the toxic intermediate in alzheimer's disease neurodegeneration.
  80. Phosphorylation of amyloid-beta at the serine 26 residue by human cdc2 kinase.
  81. Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2.
  82. PR: Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence.
  83. (1995). Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling.
  84. Purinergic signalling and disorders of the central nervous system.
  85. RJ: Decreased clearance of CNS beta-amyloid in Alzheimer's disease.
  86. Rossner S: Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology.
  87. (2003). Saido TC: Alzheimer's disease, neuropeptides, neuropeptidase, and amyloid-beta peptide metabolism. Sci Aging Knowledge Environ
  88. Saido TC: Metabolism of amyloid-beta peptide and Alzheimer's disease. Pharmacol Ther 2005;108:129-
  89. (1993). Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell
  90. Selkoe DJ: A beta oligomers - a decade of discovery.
  91. Selkoe DJ: Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers.
  92. (1992). Selkoe DJ: Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production.
  93. (1999). Selkoe DJ: Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons.
  94. Selkoe DJ: Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid betapeptide.
  95. Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
  96. Selkoe DJ: The APP family of proteins: similarities and differences.
  97. Shirasawa T: Isoaspartate formation and neurodegeneration in Alzheimer's disease.
  98. (1999). Sitkovsky MV: Ecto-protein kinases: ecto-domain phosphorylation as a novel target for pharmacological manipulation? Trends Pharmacol Sci
  99. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior.
  100. (1994). Synthetic post-translationally modified human A beta peptide exhibits a markedly increased tendency to form betapleated sheets in vitro.
  101. T: Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5.
  102. (2008). Takashima A: Amyloid oligomer conformation in a group of natively folded proteins. PLoS One
  103. Takio K: Racemization: its biological significance on neuropathogenesis of Alzheimer's disease.
  104. (1994). Teplow DB: Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor.
  105. (1996). The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol Med
  106. The cell biology of Alzheimer's disease: uncovering the secrets of secretases.
  107. The functions of mammalian amyloid precursor protein and related amyloid precursor-like proteins.
  108. Tuning the conformation properties of a peptide by glycosylation and phosphorylation.
  109. (1989). V: Evidence for ecto-protein kinase activity that phosphorylates Kemptide in a cyclic AMP-dependent mode.
  110. (1995). VM: Relationship between plaques, tangles, and dystrophic processes in Alzheimer's disease.
  111. WL: Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease.
  112. (1998). WL: Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
  113. WL: Synaptic targeting by Alzheimer's-related amyloid beta oligomers.
  114. (1994). Yankner BA: Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.
  115. YR: Folding stability of amyloid-beta 40 monomer is an important determinant of the nucleation kinetics in fibrillization.