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Amyloid beta plaque: a culprit for neurodegeneration

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Abstract

Increasing life expectancy has resulted in an increase in neurodegenerative disorders like Alzheimer’s disease. None of the hypothesis proposed till date explains the exact pathobiology of the disease. It is therefore imperative to understand the underlying mechanisms. Amyloid beta (Aβ) is regarded as the main culprit and maximum therapeutic efforts are centered towards Aβ. This review will discuss about the biosynthesis, the physiological role of Aβ including the pathogenic aggregation of Aβ resulting neurodegenerative cognitive disabilities. Most studies of Alzheimer’s disease have focused on the biochemical mechanisms involved in the neurodegenerative processes triggered by Aβ aggregates. Aβ is generated from mature amyloid precursor protein being metabolized by two competing pathways, α-secretase pathway (non-amyloidogenic pathway) and β-secretase (amyloidogenic pathway). The physiological roles of Aβ reported in neurotrophic properties, neurogenesis, synaptic plasticity, metal ion sequestration and specificity of blood brain barrier. The neuronal injury is the result of Aβ oligomerization and it is reported that oligomerization of Aβ contributes to neurodegeneration in Alzheimer’s disease. The physiological role of Aβ must be considered in the development of medications that intended to decrease its oligomerization forming plaques in a disease like Alzheimer’s disease. The biosynthetic pathways for transport and accumulation of Aβ need to be ascertained as an attempt to develop future strategies for prevention of neurodegenerative disorders.

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References

  1. Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer’s 1907 paper Uber eineeigenartige Erkankung der Hirnrinde. Clin Anat 8:429–431

    Article  CAS  PubMed  Google Scholar 

  2. Nelson R, Sawaya MR, Balbirnie M, Madsen AO, Riekel C (2005) Structure of the cross-beta spine of amyloid-like fibrils. Nature 435:773–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Ann Rev Neurosci 26:267–298

    Article  CAS  PubMed  Google Scholar 

  4. Ramirez-Alvarado M, Merkel JS, Regan L (2000) A systematic exploration of the influence of the protein stability on amyloid fibril formation in vitro. Proc Natl Acad Sci 97(16):8979–8984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gandy S (2005) The role of cerebral amyloid β accumulation in common forms of Alzheimer’s disease. J Clin Invest 115:1121–1129

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pietri M (2013) PDK1 decreases TACE-mediated alpha-secretase activity and promotes disease progression in prion and Alzheimer’s diseases. Nat Med 245(654):342–349

    Google Scholar 

  7. Golde TE (2013) Gamma-secretase inhibitors and modulators. Biochem Biophys Acta 356:245–267

    Google Scholar 

  8. Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW (1991) In vitro aging of beta amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 563:311–314

    Article  CAS  PubMed  Google Scholar 

  9. Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P (1995) Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16:285–298

    Article  CAS  PubMed  Google Scholar 

  10. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  11. Korczyn AD (2008) The amyloid cascade hypothesis. Alzheim. Dementia 4:176–178

    Article  CAS  Google Scholar 

  12. Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200

    Article  CAS  PubMed  Google Scholar 

  13. Edwards DR, Handsley M, Pennington CJ (2008) The ADAM metalloproteinase’s. Mol Asp Med 29(5):258–289

    Article  CAS  Google Scholar 

  14. Shoji M (1992) Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258(5079):126–129

    Article  CAS  PubMed  Google Scholar 

  15. Chang KA, Suh YH (2010) Possible roles of amyloid intracellular domain of amyloid precursorprotein. BMB Rep 43(10):656–663

    Article  CAS  PubMed  Google Scholar 

  16. Zhang H (2011) Proteolytic processing of Alzheimer’s beta-amyloid precursor protein. J Neurochem 1(1):9–21

    CAS  Google Scholar 

  17. Vanessa de Jesus R, Guimarães FM, Diniz BS, Forlenza OV (2009) Neurobiological pathways to Alzheimer’s disease: amyloid-beta, Tau protein or both? Dement Neuropsychol 24(1):234–245

    Google Scholar 

  18. Ko¨gel D, Deller T, Behl C (2011) Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging. Exp Brain Res 2211:121–143

    Google Scholar 

  19. Wilquet V, De Strooper B (2004) Amyloid-beta precursor protein processing in neurodegeneration. Curr Opin Neurobiol 14:582–588

    Article  CAS  PubMed  Google Scholar 

  20. Lazo ND, Maji SK, Fradinger EA, Bitan G, Teplow DB (2004) The amyloid β protein. Am J Pathol 56:384–491

    Google Scholar 

  21. Miller DL, Papayannopoulos IA, Styles J, Bobin SA, Lin YY, Biemann K (1993) Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer’s disease. Arch Biochem Biophys 301:41–52

    Article  CAS  PubMed  Google Scholar 

  22. Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, Ball MJ (1993) Beta-Amyloid is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci 90:10836–10840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Iwatsubo T, Mann DM, Odaka A, Suzuki N, Ihara Y (1995) Amyloid beta protein (A beta) deposition: Abeta 42(43) precedes Abeta 40 in Down syndrome. Ann Neurol 37:294–299

    Article  CAS  PubMed  Google Scholar 

  24. Suzuki N, Iwatsubo T, Odaka A, Ishibashi Y, Kitada C, Ihara Y (1994) High tissue content of soluble beta 1-40 is linked to cerebral amyloid angiopathy. Am J Pathol 145:452–460

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Plant LD (2003) The production of amyloid beta peptide is a critical requirement for the plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci 23(13):5531–5535

    CAS  PubMed  Google Scholar 

  26. Cirrito JR (2003) In vivo assessment of brain interstitial fluid with micro dialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci 23(26):8844–8853

    CAS  PubMed  Google Scholar 

  27. Atwood CS (2003) Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev 43(1):1–16

    Article  CAS  PubMed  Google Scholar 

  28. Hughes JR (1958) Post-tetanic potentiation physiological reviews. Exp Brain Res 34(1):91–113

    Google Scholar 

  29. Walsh DM (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880):535–539

    Article  CAS  PubMed  Google Scholar 

  30. Nalivaeva NN, Turner AJ (2013) The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett 587(13):2046–2054

    Article  CAS  PubMed  Google Scholar 

  31. Kohli BM (2012) Interactome of the amyloid precursor protein APP in brain reveals a protein network involved in synaptic vesicle turnover and a close association with Synaptotagmin-1. J Proteome Res 11(8):4075–4090

    Article  CAS  PubMed  Google Scholar 

  32. Octave JN (2013) From synaptic spines to nuclear signaling: nuclear and synaptic actions of the amyloid precursor protein. J Neurochem 126(2):183–190

    Article  CAS  PubMed  Google Scholar 

  33. Puzzo D (2011) Endogenous amyloid-beta is necessary for hippocampal synaptic plasticity and memory. Ann Neurol 69(5):819–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Smith DG, Cappai R, Barnham KJ (2007) The redox chemistry of the Alzheimer’s disease amyloid beta peptide. Biochem Biophys Acta 1768(8):1976–1990

    Article  CAS  PubMed  Google Scholar 

  35. Baruch R, Fischer B (2009) Abeta 40 either soluble or aggregated is a remarkably potent antioxidant in cell-free oxidative systems. Biochemistry 48(20):4354–4370

    Article  CAS  Google Scholar 

  36. Kontush A, Atwood CS (2004) Amyloid-beta: phylogenesis of a chameleon. Brain Res Rev 46(1):118–120

    Article  CAS  PubMed  Google Scholar 

  37. Curtain C (2001) Alzheimer’s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem 276(23):20466–20473

    Article  CAS  PubMed  Google Scholar 

  38. Huang X (1999) The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38(24):7609–7616

    Article  CAS  PubMed  Google Scholar 

  39. Zou K et al (2002) A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 22(12):4833-4841

    CAS  PubMed  Google Scholar 

  40. Birbrair Alexander (2013) Skeletal muscle neural proginetor cells exhibit properties of NG2-glia. Exp Cell Res 319(1):45–63

    Article  CAS  PubMed  Google Scholar 

  41. Jin K, Peel AL, Mao XO (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci 101(1):343–347

    Article  CAS  PubMed  Google Scholar 

  42. Mu Y, Gage F (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener 6:85

    Article  PubMed  PubMed Central  Google Scholar 

  43. Schulte-Herbruggen MC, Scherubl Hellweg (2008) Neurotrophins: from pathophysiology to treatment in Alzheimer’s disease. Curr Alzheimer Res 5(1):38–44

    Article  PubMed  Google Scholar 

  44. Lopez-Toledano MA, Shelanski ML (2004) Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci 24(23):5439–5444

    Article  CAS  PubMed  Google Scholar 

  45. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Nature Science 250(4978):279–282

    CAS  Google Scholar 

  46. Jan A, Gokce O, Luthi-Carter R, Lashuel HA (2008) The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity. J Biol Chem 283:28176–28189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB (2003) Amyloid beta protein (Abeta) assembly: Abeta40 and Abeta42 oligomerize through distinct pathways. Proc Nat Aca Sci 100:330–335

    Article  CAS  Google Scholar 

  48. Harper JD, Lansbury PT (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 66:385–407

    Article  CAS  PubMed  Google Scholar 

  49. Taylor BM, Sarver RW, Fici G, Poorman RA, Lutzke BS, Molinari A (2003) Spontaneous aggregation and cytotoxicity of the β-amyloid Aβ1-40: a kinetic model. Biochemistry 22:31–40

    CAS  Google Scholar 

  50. LaFerla (2002) Calcium dyshomeostasis and intracellular signaling in Alzheimer’s disease. Nature Review Neurosci 3(1):862–872

    Article  CAS  Google Scholar 

  51. Wang HY, Lee DHS, Andrea MR, Peterson PA, Shank RP, Reitz AB (2000) β-Amyloid (1-42) binds to alpha 7 nicotinic acetylcholine receptor with high affinity: implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632

    Article  CAS  PubMed  Google Scholar 

  52. Arispe N, Diaz JC, Simakova O (2007) Aβ ion channels: prospects for treating Alzheimer’s disease with Aβ channel blockers. Biochim Biophys Acta 1768:1952–1965

    Article  CAS  PubMed  Google Scholar 

  53. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST (2007) Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590–11601

    Article  CAS  PubMed  Google Scholar 

  54. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG (2005) Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280:17294–17300

    Article  CAS  PubMed  Google Scholar 

  55. Kelly BL, Ferreira A (2006) βAmyloid-induced dynamin -1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons. J Biol Chem 281:28079–28089

    Article  CAS  PubMed  Google Scholar 

  56. Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J (2009) A role for synaptic zinc in activity-dependent Aβ oligomer formation and accumulation at excitatory synapses. J Neurosci 29:4004–4015

    Article  CAS  PubMed  Google Scholar 

  57. Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D (2009) Soluble oligomers of amyloid Aβ protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62:788–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shankar GM, Blood good BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–2875

    Article  CAS  PubMed  Google Scholar 

  59. Sanz-Blasco S, Valero RA, Rodríguez-Crespo I, Villalobos C, Núñez L (2008) Mitochondrial Ca2+ overload underlies Aβ oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS One 3(1):2718–2809

    Article  CAS  Google Scholar 

  60. Pfrieger FW (2005) Cholesterol: a Major dietary factor regulating formation of amyloid beta. Biochim Biophys Acta 1610:271–280

    Article  CAS  Google Scholar 

  61. Bodovitz S, Klein WL (1996) Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 271:4436–4440

    Article  CAS  PubMed  Google Scholar 

  62. Ikezu T, Trapp BD, Song KS, Schlegel A, Lisanti MP, Okamoto T (1998) Caveolae, plasma membrane microdomains for alpha-secretase mediated processing of the amyloid precursor protein. J Biol Chem 273:10485–10495

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to Shoolini University, Solan, HP for providing facilities of data base for exhaustive literature survey.

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  1. School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173212, India

    Ankita Gupta & Rohit Goyal

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  1. Ankita Gupta
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Correspondence to Rohit Goyal.

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Gupta, A., Goyal, R. Amyloid beta plaque: a culprit for neurodegeneration. Acta Neurol Belg 116, 445–450 (2016). https://doi.org/10.1007/s13760-016-0639-9

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