|Molecular structures of Aß oligomers and Aß fibers.
Photo: Courtesy of Dr. Zhefeng Guo
Current Alzheimer’s drugs aim to reduce the amyloid plaques — sticky deposits that build up in the brain — that are a visual trademark of the disease. These plaques are made of long fibers of a protein called amyloid beta, or Aß. Recent studies, however, suggest that the real culprit behind Alzheimer’s may be small Aß clumps, called oligomers, that appear in the brain years before plaques develop.
In unraveling the molecular structure of oligomers, UCLA scientists, led by Zhefeng Guo, PhD, assistant professor of neurology and a member of UCLA’s Brain Research Institute and Molecular Biology Institute, discovered that Aß has a vastly different organization in oligomers than in amyloid plaques. Their finding could shed light on why Alzheimer’s drugs designed to seek out amyloid plaques have no effect on oligomers; the study suggests that the drugs failed in clinical trials because they zero in on plaques and do not work on oligomers. Future studies on oligomers will help speed the development of new drugs specifically aiming at Aß oligomers, the researchers say.
“Teasing Out the Structural Details of an Oligomer Involved in Alzheimer Disease: Structural Insights into Aß42 Oligomers Using Site-directed Spin Labeling,” Journal of Biological Chemistry, June 28, 2013