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American Journal of Alzheimer's Disease and Other Dementias®
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Antioxidant protection and neurodegenerative disease: The role of amyloid-ß and tau

Rudy J. Castellani, MD

Department of Pathology, University of Maryland, Baltimore, Maryland

Hyoung-gon Lee, PhD

George Perry, PhD

Mark A. Smith, PhD

Department of Pathology, Case Western Reserve University, Cleveland, Ohio

In Alzheimer s disease (AD), the major components of senile plaques and neurofibrillary tangles, amyloid-ß and tau, respectively, are thought by many to play a key role in disease initiation and progression. However, herein we propose that rather than being initiators of disease pathogenesis, the lesions that characterize AD, senile plaques and neurofibrillary pathology, occur consequent to oxidative stress and, importantly, function as a primary line of antioxidant defense. Importantly, this paradigm shift in thinking about the role of lesions in disease also provides an explanation for the appearance of both amyloid-ß and tau in control individuals given the increased levels of oxidative stress associated with the aged brain. In AD, oxidative stress is not only high but chronic and is superimposed upon an age-related vulnerable environment. Therefore, one would predict, successfully, an increased lesion load in patients with AD above and beyond that seen in normal aging. The notion that amyloid-ß and tau accumulations indicate adaptation and, likely, physiological processes sheds light on the pathological expression of disease and calls into question the rationale of current therapeutic efforts targeted toward lesion removal.

Key Words: Alzheimer's disease • amyloid-ß • antioxidant • free radical • phosphorylation • redox-active metals • tau

References

  • 1. Braak H, Braak E: Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl). 1991; 82: 239-259.[CrossRef][Medline] [Order article via Infotrieve]
  • 2. Mirra SS, Heyman A, McKeel D, et al.: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part 1IL Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991; 41: 479-486.[Abstract/Free Full Text]
  • 3. Selkoe DJ: Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. JAlzheimers Dis. 2001; 3: 75-80.
  • 4. Roizen NJ, Patterson D: Down's syndrome. Lancet. 2003; 361: 1281-1289.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 5. Knowles RB, Gomez-Isla T, Hyman BT: Abeta associated neuropil changes: Correlation with neuronal loss and dementia. JNeuropathol Exp Neurol. 1998; 57: 1122-1130.[Web of Science][Medline] [Order article via Infotrieve]
  • 6. Smith MA, Joseph JA, Perry G: Arson. Tracking the culprit in Alzheimer's disease. Ann N YAcadSci. 2000; 924: 35-38.
  • 7. Nunomura A, Perry G, Pappolla MA, et al.: Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol. 2000; 59: 1011-1017.[Web of Science][Medline] [Order article via Infotrieve]
  • 8. Nunomura A, Perry G. Aliev G; et al.: Oxidative damage is the earliest event in Alzheimer disease. JNeuropathol Exp Neurol. 2001; 60: 759-767.[Web of Science][Medline] [Order article via Infotrieve]
  • 9. Yan SD, Yan SF, Chen X, et al.: Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med. 1995; 1: 693-699.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 10. Tamagno E, Parola M, Bardini P, et al.: Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. JNeurochem. 2005; 92: 628-636.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 11. van Groen T, Puurunen K, Maki HM, et al.: Transformation of diffuse beta-amyloid precursor protein and beta-amyloid deposits to plaques in the thalamus after transient occlusion of the middle cerebral artery in rats. Stroke. 2005; 36: 1551-1556.[Abstract/Free Full Text]
  • 12. Cuajungco MP, Goldstein LE, NunomuraA, et al.: Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redoxsilencing and entombment of abeta by zinc. JBiol Chem. 2000; 275: 19439-19442.[Abstract/Free Full Text]
  • 13. Davis DG, Schmitt FA, Wekstein DR, et al.: Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol. 1999; 58: 376-388.[Web of Science][Medline] [Order article via Infotrieve]
  • 14. Pike CJ, Walencewicz AJ, Glabe CG, et al.: Aggregation-related toxicity of synthetic beta-amyloid protein in hippocampal cultures. Eur JPharmacol. 1991; 207: 367-368.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 15. Huang X, Cuajungco MP, Atwood CS, et al.: Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999; 274: 3711l-37116.
  • 16. Boyd-Kimball D, Sultana R, Abdul HM, et al.: Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(I -42)-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease. JNeurosci Res. 2005; 79: 700-706.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 17. Boyd-Kimball D, Sultana R, Poon HF, et al.: Gamma-glutamylcysteine ethyl ester protection of proteins from Abeta(1-42)-mediated oxidative stress in neuronal cell culture: A proteomics approach. J Neurosci Res. 2005; 79: 707-713.[CrossRef][Medline] [Order article via Infotrieve]
  • 18. Rottkamp CA, Raina AK, Zhu X, et al.: Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med. 2001; 30: 447-450.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 19. Frautschy SA, Cole GM, Baird A: Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid. AmrJPathol. 1992; 140: 1389-1399.
  • 20. Canning DR, McKeon RJ, DeWitt DA, et al.: Beta-amyloid of Alzheimer's disease induces reactive gliosis that inhibits axonal outgrowth. Exp Neurol. 1993; 124: 289-298.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 21. DeWitt DA, Perry G, Cohen M, et al.: Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease. Exp Neurol. 1998; 149: 329-340.[CrossRef][Medline] [Order article via Infotrieve]
  • 22. Walter MF, Mason P, Mason RP: Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997; 233: 760-764.[CrossRef][Medline] [Order article via Infotrieve]
  • 23. Davies L, Wolska B, Hilbich C, et al.: A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: Prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology. 1988; 38: 1688-1693.[Abstract/Free Full Text]
  • 24. McLean CA, Cherny RA, Fraser FW, et al.: Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999; 46: 860-866.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 25. Xia W, Zhang J, Kholodenko D, et al.: Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins. J Biol Chem. 1997; 272: 7977-7982.[Abstract/Free Full Text]
  • 26. Walsh DM, Klyubi I, Fadeeva JV, et al.: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal longterm potentiation in vivo. Nature. 2002; 416: 535-539.[CrossRef][Medline] [Order article via Infotrieve]
  • 27. Walsh DM, Townsend M, Podlisny MB, et al.: Certain inhibitors of synthetic amyloid betapeptide (Abeta) fibrillogenesis, block oligomerization of natural Abeta and thereby rescue long-term potentiation. JNeurosci. 2005; 25: 2455-2462.[Abstract/Free Full Text]
  • 28. Joseph JA, Shukitt-Hale B, Denisova NA, et al.: Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. JNeurosci. 1998; 18: 8047-8055.[Abstract/Free Full Text]
  • 29. Joseph JA, Shukitt-Hale B, Denisova NA, et al.: Reversals of agerelated declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. JNeurosci. 1999; 19: 8114-8121.[Abstract/Free Full Text]
  • 30. Bickford PC, Gould T, BriederickL, et al.: Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats. Brain Res. 2000; 866: 211-217.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 31. Casadesus G, Shukitt-Hale B, Stellwagen HM, et al.: Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci. 2004; 7: 309-316.[CrossRef][Medline] [Order article via Infotrieve]
  • 32. Lee HG, Perry G, Moreira Pi, et al.: Tau phosphorylation in Alzheimer's disease: Pathogen or protector? Trends Mol Med. 2005; 11: 164-169.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 33. Takeda A, Perry G. Abraham NQG et al.: Overexpression of heme oxygenase in neuronal cells, the possible interaction with Tau. JBiol Chem. 2000; 275: 5395-5399.[Abstract/Free Full Text]
  • 34. Long JM, Mouton PR, Jucker M et al.: What counts in brain aging? Design-based stereological analysis of cell number. J Gerontol A Biol Sci Med Sci. 1999; 54: B407-417.[Abstract]
  • 35. Hsiao K, Chapman P, Nilsen S, et al.: Correlative memory deficits, Abeta elevation, -and amyloid plaques in transgenic mice. Science. 1996; 274: 99-102.[Abstract/Free Full Text]
  • 36. Pappolla MA, Chyan YJ, Omar RA, et al.: Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: A chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol. 1998; 152: 871-877.[Abstract]
  • 37. Smith MA, Hirai K, Hsiao K, et al.: Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998; 70: 2212-2215.[Web of Science][Medline] [Order article via Infotrieve]
  • 38. Pratico D, Uryu K, Leight S, et al.: Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. JNeurosci. 2001; 21: 4183-4187.[Abstract/Free Full Text]
  • 39. Smith MA, Kutty RK, Richey PL, et al.: Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease. Am JPathol. 1994; 145: 42-47.[Abstract]
  • 40. Mori H, Kondo J, Ihara Y: Ubiquitin is a component of paired helical filaments inAlzheimer's disease. Science. 1987; 235: 1641-1644.[Abstract/Free Full Text]
  • 41. Perry G. Friedman R, Shaw G. et al.: Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. ProcNatlAcadSci USA. 1987; 84: 3033-3036.[Abstract/Free Full Text]
  • 42. Calhoun ME, Wiederhold KH, Abramowski D, et al.: Neuron loss inAPPtransgenic mice. Nature. 1998; 395: 755-756.[CrossRef][Medline] [Order article via Infotrieve]
  • 43. Joseph J, Shukitt-Hale B, Denisova NA, et al.: Copernicus revisited: amyloid beta inAlzheimer's disease. NeurobiolAging. 2001; 22: 131-146.[CrossRef][Medline] [Order article via Infotrieve]
  • 44. Gordon MN, King DL, Diamond DM, et al.: Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS 1 mice. Neurobiol Aging. 2001; 22: 377-385.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 45. Gomez-Isla T, Hollister R, West H, et al.: Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann Neurol. 1997; 41: 17-24.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 46. Kril JJ, Patel S. Harding AJ, et al.: Neuron loss from the hippocampus of Alzheimer's disease exceeds extracellular neurofibrillary tangle formation. Acta Neuropathol (Berl). 2002; 103: 370-376.[CrossRef][Medline] [Order article via Infotrieve]
  • 47. Nunomura A, Perry G, Pappolla MA, et al.: RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci. 1999; 19: 1959-1964.[Abstract/Free Full Text]
  • 48. Smith MA, Rudnicka-Nawrot M, Richey PL, et al.: Carbonylrelated posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease. J Neurochem. 1995; 64: 2660-2666.[Web of Science][Medline] [Order article via Infotrieve]
  • 49. Sayre LM, Zelasko DA, Harris PL, et al.: 4-Hydroxynonenalderived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem. 1997; 68: 2092-2097.[Web of Science][Medline] [Order article via Infotrieve]
  • 50. Liu Q, Smith MA, Avila J, et al.: Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations. Free Radic Biol Med. 2005; 38: 746-754.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 51. Takeda A, Smith MA, Avila J, et al.: In Alzheimer's disease, heme oxygenase is coincident with Alz5O, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J Neurochem. 2000; 75: 1234-1241.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 52. Calingasan NY, Uchida K, Gibson GE: Protein-bound acrolein: A novel marker of oxidative stress in Alzheimer's disease. J Neurochem. 1999; 72: 751-756.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 53. Morsch R, Simon W, Coleman PD: Neurons may live for decades with neurofibrillary tangles. JNeuropathol Exp Neurol. 1999; 58: 188-197.[Web of Science][Medline] [Order article via Infotrieve]
  • 54. Wataya T, Nunomura A, Smith MA, et al.: High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. JBiol Chem. 2002; 277: 4644-4648.[Abstract/Free Full Text]
  • 55. Zhu X, Rottkamp CA, Boux H, et al.: Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol. 2000; 59: 880-888.[Web of Science][Medline] [Order article via Infotrieve]
  • 56. Zhu X, Rottkamp CA, Hartzler A, et al.: Activation of MKK6, an upstream activator of p38, in Alzheimer's disease. JNeurochem. 2001; 79: 311-318.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 57. Zhu X, Castellani RJ, Takeda A, et al.: Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: The ‘two hit’ hypothesis. MechAgeingDev. 2001; 123: 39-46.
  • 58. Zhu X, Raina AK, Rottkamp CA, et al.: Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. JNeurochem. 2001; 76: 435-441.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 59. Castellani R, Smith MA, Richey PL, et al.: Evidence for oxidative stress in Pick disease and corticobasal degeneration. Brain Res. 1995; 696: 268-271.[CrossRef][Medline] [Order article via Infotrieve]
  • 60. Odetti P, Garibaldi S, Norese R, et al.: Lipoperoxidation is selectively involved in progressive supranuclear palsy. JNeuropathol Exp Neurol. 2000; 59: 393-397.[Medline] [Order article via Infotrieve]
  • 61. Gerst JL, Siedlak SL, Nunomura A, et al.: Role of oxidative stress in frontotemporal dementia. Dement Geriatr Cogn Disord. 1999; 10 Suppl 1: 85-87.[Medline] [Order article via Infotrieve]
  • 62. Ekinci FJ, Shea TB: Phosphorylation of tau alters its association with the plasma membrane. Cell Mol Neurobiol. 2000; 20: 497-508.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 63. Arrasate M, Mitra S, Schweitzer ES, et al.: Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004; 431: 805-810.[CrossRef][Medline] [Order article via Infotrieve]
  • 64. Perry G, Nunomura A, Raina AK, et al.: Amyloid-beta junkies. Lancet. 2000; 355: 757-757.[Medline] [Order article via Infotrieve]
  • 65. Smith MA, Atwood CS, Joseph JA, et al.: Predicting the failure of amyloid-beta vaccine. Lancet. 2002; 359: 1864-1865.[Medline] [Order article via Infotrieve]
  • 66. Rottkamp CA, Atwood CS, Joseph JA, et al.: The state versus amyloid-beta: The trial of the most wanted criminal in Alzheimer disease. Peptides. 2002, 23: 1333-1341.[CrossRef][Medline] [Order article via Infotrieve]
  • 67. Smith MA, Casadesus G. Joseph JA, et al.: Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002; 33: 1194-1199.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 68. Lee HQ, Casadesus G. Zhu X, et al.: Challenging the amyloid cascade hypothesis: Senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann N YAcad Sci. 2004; 1019: 1-4.[CrossRef][Medline] [Order article via Infotrieve]

American Journal of Alzheimer's Disease and Other Dementias®, Vol. 21, No. 2, 126-130 (2006)
DOI: 10.1177/153331750602100213
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