Alzheimer’s disease (AD) is a protein misfolding disease characterized by a buildup of ß-amyloid (Aß) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aß peptide-plasma membrane interactions. Recent evidence suggests that fibril-like, small Aß oligomers are the toxic species in AD.1 These oligomers contain ß-sheet structure and present exposed hydrophobic surface. Oligomers with this motif are capable of penetrating the cell membrane and gathering to form toxic ion channels.2 Understanding the exact nature by which these channels conduct electrical and molecular signals could aid in identifying potential therapeutic targets for the prevention and treatment of AD.3 Since no experiment-based Aß channel structures at atomic resolution are currently available, molecular dynamics (MD) simulations have successfully provided the atomic-level details of three-dimensional Aß channel conformations embedded in the membranes. The predicted structural models by MD support that the Aß channel is an assembly of loosely associated mobile ß-sheet subunits. The emerging picture from our large-scale simulations is that toxic ion channels formed by ß-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. Our observations support the amyloid channel hypothesis that Aß oligomers can irreversibly insert into a membrane and spontaneously form an ion channel, leading to cell death in AD. We further suggest that Aß-directed therapeutics should consider a combination therapy that targets the toxic Aß oligomers on the membrane before they are inserted, and, in parallel, the oligomers that have already penetrated into the membrane, where these agents could prevent toxic channel formations.
Ruth Nussinov,1,2 Hyunbum Jang,1 Ratnesh Lal,3 Bruce L. Kagan4
1Basic Science Program, SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States
2Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
3Departments of Bioengineering and Mechanical and Aerospace Engineering and Material Science Program, University of California, San Diego, La Jolla, California 92093, United States
4Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90024, United States