Posts Tagged ‘NSF’
Article by: Nicole Casal Moore
ANN ARBOR—Exactly how Alzheimer’s disease kills brain cells is still somewhat of a mystery, but University of Michigan researchers have uncovered a clue that supports the idea that small proteins prick holes into neurons.
The team also found that a certain size range of clumps of these proteins are particularly toxic to cells, while smaller and larger aggregates of the protein appear to be benign.
The findings, which appear in the journal PLOS ONE, add important detail to the knowledge base regarding this disease that affects 5.4 million Americans in 2012 but remains incurable and largely untreatable. The results could potentially help pharmaceutical researchers target drugs to the right disease mechanisms.
The U-M findings strongly support the idea that amyloid peptides damage the membrane around nerve cells and lead to uncontrolled movement of calcium ions into them. Calcium signaling is an important way that cells communicate and healthy cells regulate its flow precisely. The toxic mechanism implicated in the new study could act on its own or together with the other proposed courses and ultimately lead to a loss of brain cells in patients, the researchers say.
“There’s a good chance Alzheimer’s is caused, at least in part, by four- to 13-peptide aggregates that punch holes in cells and kill them gradually after prolonged exposure,” said Michael Mayer, an associate professor of biomedical engineering and chemical engineering who led the research.
“The size range of amyloid clumps that we identified as the most pore-forming was also the most toxic. The correlation is staggering. In the conditions of the culture dish, these results strongly suggest that pore formation by amyloid-beta is responsible for neuronal cell death.”
Using observation and sophisticated statistical analysis, the team explored whether the peptides’ tendency to poke holes in cell membranes correlated with the death of actual cells under the same conditions.
To conduct the experiment, Panchika Prangkio, a Ph.D. student in Mayer’s lab, formed amyloid-beta aggregates in water over 0, 1, 2, 3, 10 and 20 days. She measured how well amyloid clumps of various sizes punched pores in a lipid bilayer that mimicked a cell membrane. And, separately, but with the same amyloid samples, the team observed how many cells died and determined which size amyloids were in the sample at each time point. The researchers used cells from a human nerve cell cancer line.
Their finding that mid-size amyloid clumps are most toxic supports recent theories that individual peptides as well as longer amyloid fibers might be protective, rather than harmful, the researchers say. The smallest and largest aggregates were negatively correlated with cell death, which suggests they may bind with the dangerous mid-length clumps and trap them in a nontoxic form.
The work could help advance the search for Alzheimer’s treatments that would work by blocking pore formation by mid-sized amyloid-beta clumps. And they could raise questions about the potential efficacy of drugs (such as Bapineuzumab) that aim to remove large aggregates of amyloid beta
“The better the research community understands how Alzheimer’s operates, the more likely we are to develop effective treatment,” Mayer said.
The paper is titled “Multivariate analyses of amyloid-beta oligomer populations indicate a connection between pore formation and cytotoxicity.” It is a collaborative effort with the research group of Jerry Yang, an associate professor of chemistry and biochemistry at the University of California, San Diego, and David Sept, an associate professor of biomedical engineering at U-M. Funding was provided by the Wallace H. Coulter Foundation with support from the Alzheimer’s Association, the National Science Foundation and the government of Thailand.
- Study: www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047261
- Michael Mayer: www.bme.umich.edu/labs/biomembrane
- Link to original News Services article: http://www.ns.umich.edu/new/releases/20884-understanding-alzheimer-s-study-gives-insights-into-how-disease-kills-brain-cells
BME Ph.D. students at U-M BME have secured three new distinctions for 2012. Congratulations, Kelly, Aftin, and Shani, and keep up the great work!
Kelly Carnahan, BME Ph.D. Student working with Professor Jan Stegemann in the Cell-Matrix Interactions & Tissue Engineering (CMITE) Lab, won a 2012 NSF Fellowship as part of the Graduate Research Fellowship Program (GRFP).
Aftin Ross, BME Ph.D. Student working with Professor Joerg Lahann, was selected as a scholar for the Whitaker Scholars Fellowship Program and will complete a 1 year postdoctoral appointment at the Karlsruhe Institute of Technology in Karlsruhe, Germany.
Shani Ross, BME Ph.D. Student working with Professor J. Wayne Aldrige from the Department of Psychology, won the Outstanding Graduate Student Instructor Award sponsored by the University of Michigan – Rackham Graduate School. This award honors GSIs who have exceptional ability and creativity as teachers, exhibit continuous growth as a teacher, offer outstanding mentorship to their students, and show growth as scholars in the course of their graduate programs.
Sasha Cai Lesher-Perez, a Ph.D. student in Professor Shuichi Takayama’s Micro/Nano/Molecular Biotechnology Research Lab, and Ram Rao, a Ph.D. student in Professor Jan Stegemann’s Cell Matrix Interactions & Tissue Engineering (CMITE) Laboratory, were recipients of the 2011 NSF Graduate Research Fellowship Program (GFRP) Award. The purpose of the National Science Foundation’s Graduate Research Fellowship Program is to ensure the vitality of the human resource base of science and engineering in the United States and to reinforce its diversity. THE NSF Graduate Research Fellowship Program is the oldest fellowship of its kind and has a history of selecting recipients who achieve high levels of success in their future professional careers. The fellowship provides three years of support for graduate study leading to research-based masters or doctoral degrees in Science, Technology, Engineering and Mathematics (STEM) fields.