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A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization

Gal Bitan1, Bogdan Tarus, Sabrina S Vollers

  • 1Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.

Journal of the American Chemical Society
|December 11, 2003
PubMed

Insights

Oxidizing methionine-35 in amyloid beta-42 (Abeta42) prevents toxic paranuclei formation, a key step in Alzheimer

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Aberrant protein oligomerization, particularly amyloid beta-protein (Abeta) in Alzheimer's disease (AD), drives neurotoxicity.
  • Amyloid beta-42 (Abeta42) forms distinct toxic oligomers (paranuclei) compared to Abeta40, correlating with AD pathogenesis.

Purpose of the Study:

  • To identify structural elements governing Abeta42 paranucleus formation.
  • To explore Met(35) oxidation as a strategy to inhibit toxic Abeta42 oligomerization for AD treatment.

Main Methods:

  • Investigated the role of methionine-35 (Met(35)) in Abeta42 oligomerization.
  • Systematically altered the C(gamma)(35)-substituent group of Abeta42.
  • Analyzed oligomer size and morphology.

Main Results:

  • Oxidation of Met(35) in Abeta42 blocked paranucleus formation.
  • Oxidized Abeta42 produced oligomers similar to Abeta40.
  • Electronic properties of the C(gamma)(35)-substituent, not size, controlled oligomerization pathway.

Conclusions:

  • Selective Met(35) oxidation inhibits toxic Abeta42 paranuclei assembly.
  • This targeted oxidation presents a potential therapeutic strategy for Alzheimer's disease.

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