Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1998 Feb;152(2):367–372.

Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders.

A Takeda 1, M Mallory 1, M Sundsmo 1, W Honer 1, L Hansen 1, E Masliah 1
PMCID: PMC1857971  PMID: 9466562

Abstract

The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as a-synuclein) is a presynaptic terminal molecule that accumulates in the plaques of Alzheimer's disease. Recent studies have shown that a mutation in NACP is associated with familial Parkinson's disease, and that Lewy bodies are immunoreactive with antibodies against this molecule. To clarify the patterns of accumulation and differences in abnormal compartmentalization, we studied NACP immunoreactivity using double immunolabeling and laser scanning confocal microscopy in the cortex of patients with various neurodegenerative disorders. In Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease, NACP was found to immunolabel cortical Lewy bodies, abnormal neurites, and dystrophic neurites in the plaques. Double-labeling studies showed that all three of these neuropathological structures also contained ubiquitin, synaptophysin, and neurofilament (but not tau) immunoreactivity. In contrast, neurofibrillary tangles, neuropil threads, Pick bodies, ballooned neurons, and glial tangles (most of which were tau positive) were NACP negative. These results support the view that NACP specifically accumulates in diseases related to Lewy bodies such as Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease and suggests a role for this synaptic protein in the pathogenesis of neurodegeneration.

Full text

PDF
367

Images in this article

369Figure 1
on p.369
369Figure 2
on p.369
370Figure 3
on p.370

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai H., Lee V. M., Hill W. D., Greenberg B. D., Trojanowski J. Q. Lewy bodies contain beta-amyloid precursor proteins of Alzheimer's disease. Brain Res. 1992 Jul 10;585(1-2):386–390. doi: 10.1016/0006-8993(92)91242-7. [DOI] [PubMed] [Google Scholar]
  2. Dickson D. W., Ruan D., Crystal H., Mark M. H., Davies P., Kress Y., Yen S. H. Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD. Neurology. 1991 Sep;41(9):1402–1409. doi: 10.1212/wnl.41.9.1402. [DOI] [PubMed] [Google Scholar]
  3. Gai W. P., Blessing W. W., Blumbergs P. C. Ubiquitin-positive degenerating neurites in the brainstem in Parkinson's disease. Brain. 1995 Dec;118(Pt 6):1447–1459. doi: 10.1093/brain/118.6.1447. [DOI] [PubMed] [Google Scholar]
  4. George J. M., Jin H., Woods W. S., Clayton D. F. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron. 1995 Aug;15(2):361–372. doi: 10.1016/0896-6273(95)90040-3. [DOI] [PubMed] [Google Scholar]
  5. Han H., Weinreb P. H., Lansbury P. T., Jr The core Alzheimer's peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: is NAC a common trigger or target in neurodegenerative disease? Chem Biol. 1995 Mar;2(3):163–169. doi: 10.1016/1074-5521(95)90071-3. [DOI] [PubMed] [Google Scholar]
  6. Honer W. G., Falkai P., Young C., Wang T., Xie J., Bonner J., Hu L., Boulianne G. L., Luo Z., Trimble W. S. Cingulate cortex synaptic terminal proteins and neural cell adhesion molecule in schizophrenia. Neuroscience. 1997 May;78(1):99–110. doi: 10.1016/s0306-4522(96)00489-7. [DOI] [PubMed] [Google Scholar]
  7. Irizarry M. C., Kim T. W., McNamara M., Tanzi R. E., George J. M., Clayton D. F., Hyman B. T. Characterization of the precursor protein of the non-A beta component of senile plaques (NACP) in the human central nervous system. J Neuropathol Exp Neurol. 1996 Aug;55(8):889–895. doi: 10.1097/00005072-199608000-00004. [DOI] [PubMed] [Google Scholar]
  8. Iwai A., Masliah E., Sundsmo M. P., DeTeresa R., Mallory M., Salmon D. P., Saitoh T. The synaptic protein NACP is abnormally expressed during the progression of Alzheimer's disease. Brain Res. 1996 May 13;720(1-2):230–234. doi: 10.1016/0006-8993(96)00014-5. [DOI] [PubMed] [Google Scholar]
  9. Iwai A., Masliah E., Yoshimoto M., Ge N., Flanagan L., de Silva H. A., Kittel A., Saitoh T. The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron. 1995 Feb;14(2):467–475. doi: 10.1016/0896-6273(95)90302-x. [DOI] [PubMed] [Google Scholar]
  10. Iwai A., Yoshimoto M., Masliah E., Saitoh T. Non-A beta component of Alzheimer's disease amyloid (NAC) is amyloidogenic. Biochemistry. 1995 Aug 15;34(32):10139–10145. doi: 10.1021/bi00032a006. [DOI] [PubMed] [Google Scholar]
  11. Jakes R., Spillantini M. G., Goedert M. Identification of two distinct synucleins from human brain. FEBS Lett. 1994 May 23;345(1):27–32. doi: 10.1016/0014-5793(94)00395-5. [DOI] [PubMed] [Google Scholar]
  12. Jensen P. H., Hojrup P., Hager H., Nielsen M. S., Jacobsen L., Olesen O. F., Gliemann J., Jakes R. Binding of Abeta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC. Biochem J. 1997 Apr 15;323(Pt 2):539–546. doi: 10.1042/bj3230539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kim H., Gearing M., Mirra S. S. Ubiquitin-positive CA2/3 neurites in hippocampus coexist with cortical Lewy bodies. Neurology. 1995 Sep;45(9):1768–1770. doi: 10.1212/wnl.45.9.1768. [DOI] [PubMed] [Google Scholar]
  14. Kim J. Evidence that the precursor protein of non-A beta component of Alzheimer's disease amyloid (NACP) has an extended structure primarily composed of random-coil. Mol Cells. 1997 Feb 28;7(1):78–83. [PubMed] [Google Scholar]
  15. Maroteaux L., Campanelli J. T., Scheller R. H. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci. 1988 Aug;8(8):2804–2815. doi: 10.1523/JNEUROSCI.08-08-02804.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Maroteaux L., Scheller R. H. The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Brain Res Mol Brain Res. 1991 Oct;11(3-4):335–343. doi: 10.1016/0169-328x(91)90043-w. [DOI] [PubMed] [Google Scholar]
  17. Masliah E., Iwai A., Mallory M., Uéda K., Saitoh T. Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer's disease. Am J Pathol. 1996 Jan;148(1):201–210. [PMC free article] [PubMed] [Google Scholar]
  18. Masliah E., Mallory M., Hansen L., Alford M., DeTeresa R., Terry R. An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer's disease. Am J Pathol. 1993 Mar;142(3):871–882. [PMC free article] [PubMed] [Google Scholar]
  19. Masliah E., Mallory M., Hansen L., DeTeresa R., Alford M., Terry R. Synaptic and neuritic alterations during the progression of Alzheimer's disease. Neurosci Lett. 1994 Jun 6;174(1):67–72. doi: 10.1016/0304-3940(94)90121-x. [DOI] [PubMed] [Google Scholar]
  20. Masliah E. Mechanisms of synaptic dysfunction in Alzheimer's disease. Histol Histopathol. 1995 Apr;10(2):509–519. [PubMed] [Google Scholar]
  21. Masliah E., Terry R. The role of synaptic proteins in the pathogenesis of disorders of the central nervous system. Brain Pathol. 1993 Jan;3(1):77–85. doi: 10.1111/j.1750-3639.1993.tb00728.x. [DOI] [PubMed] [Google Scholar]
  22. Nakajo S., Tsukada K., Omata K., Nakamura Y., Nakaya K. A new brain-specific 14-kDa protein is a phosphoprotein. Its complete amino acid sequence and evidence for phosphorylation. Eur J Biochem. 1993 Nov 1;217(3):1057–1063. doi: 10.1111/j.1432-1033.1993.tb18337.x. [DOI] [PubMed] [Google Scholar]
  23. Nishimura M., Tomimoto H., Suenaga T., Nakamura S., Namba Y., Ikeda K., Akiguchi I., Kimura J. Synaptophysin and chromogranin A immunoreactivities of Lewy bodies in Parkinson's disease brains. Brain Res. 1994 Jan 21;634(2):339–344. doi: 10.1016/0006-8993(94)91940-2. [DOI] [PubMed] [Google Scholar]
  24. Polymeropoulos M. H., Lavedan C., Leroy E., Ide S. E., Dehejia A., Dutra A., Pike B., Root H., Rubenstein J., Boyer R. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997 Jun 27;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]
  25. Sisodia S. S., Price D. L. Role of the beta-amyloid protein in Alzheimer's disease. FASEB J. 1995 Mar;9(5):366–370. doi: 10.1096/fasebj.9.5.7896005. [DOI] [PubMed] [Google Scholar]
  26. Spillantini M. G., Schmidt M. L., Lee V. M., Trojanowski J. Q., Jakes R., Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997 Aug 28;388(6645):839–840. doi: 10.1038/42166. [DOI] [PubMed] [Google Scholar]
  27. Uéda K., Fukushima H., Masliah E., Xia Y., Iwai A., Yoshimoto M., Otero D. A., Kondo J., Ihara Y., Saitoh T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11282–11286. doi: 10.1073/pnas.90.23.11282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wakabayashi K., Hansen L. A., Vincent I., Mallory M., Masliah E. Neurofibrillary tangles in the dentate granule cells of patients with Alzheimer's disease, Lewy body disease and progressive supranuclear palsy. Acta Neuropathol. 1997 Jan;93(1):7–12. doi: 10.1007/s004010050576. [DOI] [PubMed] [Google Scholar]
  29. Wakabayashi K., Honer W. G., Masliah E. Synapse alterations in the hippocampal-entorhinal formation in Alzheimer's disease with and without Lewy body disease. Brain Res. 1994 Dec 19;667(1):24–32. doi: 10.1016/0006-8993(94)91709-4. [DOI] [PubMed] [Google Scholar]
  30. Weinreb P. H., Zhen W., Poon A. W., Conway K. A., Lansbury P. T., Jr NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry. 1996 Oct 29;35(43):13709–13715. doi: 10.1021/bi961799n. [DOI] [PubMed] [Google Scholar]
  31. Yasuhara O., Matsuo A., Tooyama I., Kimura H., McGeer E. G., McGeer P. L. Pick's disease immunohistochemistry: new alterations and Alzheimer's disease comparisons. Acta Neuropathol. 1995;89(4):322–330. doi: 10.1007/BF00309625. [DOI] [PubMed] [Google Scholar]
  32. Yoshimoto M., Iwai A., Kang D., Otero D. A., Xia Y., Saitoh T. NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9141–9145. doi: 10.1073/pnas.92.20.9141. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES