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Takamura A, Okamoto Y, Kawarabayashi T, et al. Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse. Mol Neurodegener. 2011;6(1):20doi: 10.1186/1750-1326-6-20.
Takamura, A., Okamoto, Y., Kawarabayashi, T., Yokoseki, T., Shibata, M., Mouri, A., Nabeshima, T., Sun, H., Abe, K., Urisu, T., Yamamoto, N., Shoji, M., Yanagisawa, K., Michikawa, M., & Matsubara, E. (2011). Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse. Molecular neurodegeneration, 6(1), 20. https://doi.org/10.1186/1750-1326-6-20
Takamura, Ayumi, et al. "Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse." Molecular neurodegeneration vol. 6,1 (2011): 20. doi: https://doi.org/10.1186/1750-1326-6-20
Takamura A, Okamoto Y, Kawarabayashi T, Yokoseki T, Shibata M, Mouri A, Nabeshima T, Sun H, Abe K, Urisu T, Yamamoto N, Shoji M, Yanagisawa K, Michikawa M, Matsubara E. Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse. Mol Neurodegener. 2011 Mar 06;6(1):20. doi: 10.1186/1750-1326-6-20. PMID: 21375782; PMCID: PMC3061944.
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Mol Neurodegener. 2011 Mar 06;6(1):20. doi: 10.1186/1750-1326-6-20.

Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse.

Molecular neurodegeneration

Ayumi Takamura, Yasuhide Okamoto, Takeshi Kawarabayashi, Tatsuki Yokoseki, Masao Shibata, Akihiko Mouri, Toshitaka Nabeshima, Hui Sun, Koji Abe, Tsuneo Urisu, Naoki Yamamoto, Mikio Shoji, Katsuhiko Yanagisawa, Makoto Michikawa, Etsuro Matsubara

Affiliations

  1. Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan. [email protected].

PMID: 21375782 PMCID: PMC3061944 DOI: 10.1186/1750-1326-6-20

Abstract

BACKGROUND: Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined.

RESULTS: To specifically target toxic AβOs in vivo, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AβOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AβOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AβOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AβOs initiate the AD toxic process and intraneuronal AβOs may worsen neuronal degeneration and memory loss.

CONCLUSION: Now, we have evidence that HMW-AβOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.

References

  1. J Neurochem. 2007 Jan;100(1):23-35 - PubMed
  2. Science. 2002 Oct 25;298(5594):789-91 - PubMed
  3. J Neurosci. 2010 Apr 7;30(14):4845-56 - PubMed
  4. Nat Neurosci. 2002 May;5(5):452-7 - PubMed
  5. Science. 1992 Apr 10;256(5054):184-5 - PubMed
  6. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12 - PubMed
  7. Nature. 2006 Mar 16;440(7082):352-7 - PubMed
  8. Nat Neurosci. 2005 Jan;8(1):79-84 - PubMed
  9. Biochemistry. 2003 Nov 11;42(44):12749-60 - PubMed
  10. Am J Pathol. 1999 Sep;155(3):853-62 - PubMed
  11. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20324-9 - PubMed
  12. J Biol Chem. 2006 Feb 17;281(7):4292-9 - PubMed
  13. J Neurosci. 2002 Aug 1;22(15):6331-5 - PubMed
  14. Ann Neurol. 1999 Dec;46(6):860-6 - PubMed
  15. Lancet. 2008 Jul 19;372(9634):216-23 - PubMed
  16. J Neurosci. 2004 Apr 14;24(15):3801-9 - PubMed
  17. J Biol Chem. 1995 Mar 31;270(13):7563-7 - PubMed
  18. J Biol Chem. 2007 Jan 26;282(4):2646-55 - PubMed
  19. Neurobiol Aging. 2000 May-Jun;21(3):383-421 - PubMed
  20. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53 - PubMed
  21. Nat Med. 2008 Aug;14(8):837-42 - PubMed
  22. Langmuir. 2004 Aug 31;20(18):7526-31 - PubMed
  23. Nature. 2002 Apr 4;416(6880):535-9 - PubMed
  24. Mol Neurodegener. 2007 Sep 26;2:18 - PubMed
  25. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6370-5 - PubMed
  26. Science. 2003 Apr 18;300(5618):486-9 - PubMed
  27. Trends Neurosci. 2001 Apr;24(4):219-24 - PubMed
  28. Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1485-90 - PubMed
  29. FASEB J. 2007 Jul;21(9):2135-48 - PubMed
  30. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10417-22 - PubMed
  31. J Neurosci. 2004 Nov 10;24(45):10191-200 - PubMed
  32. J Biol Chem. 2009 Nov 20;284(47):32895-905 - PubMed
  33. Trends Pharmacol Sci. 1991 Oct;12(10):383-8 - PubMed
  34. Amyloid. 2002 Jun;9(2):88-102 - PubMed
  35. Brain Res. 2000 Aug 25;874(2):123-30 - PubMed
  36. J Neurochem. 2001 Nov;79(3):595-605 - PubMed

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