This new mouse mimics the genetics of the human disease more closely than any of the dozen existing mouse models and may prove more useful in the development of candidate drugs to prevent or treat the disease.
The new mouse model provides new evidence for the earliest cause of Alzheimer's, researchers report in a study to be published in the December issue of the Journal of Biological Chemistry and now available online.
The model is a cross between an existing transgenic Alzheimer's mouse and a mouse carrying fully human apoE, a gene that in one of its three variants, apoE4, is the greatest genetic risk factor for Alzheimer's in the human population.
UIC biochemist Mary Jo LaDu says amyloid-beta, a peptide, or small protein, is known to underlie the disease and is a key component of the plaques observed in the brains of deceased Alzheimer's patients at autopsy. But in addition to clumping to form those large, visible plaques, the sticky molecule is also found in smaller, soluble aggregates called oligomers -- which may be the actual culprit.
"Though for a long time it was thought that amyloid plaques might cause the nerve death seen in Alzheimer's, researchers now believe that the neurotoxicity may lie in the smaller, soluble, oligomeric forms," said LaDu, who is associate professor of anatomy and cell biology at the UIC College of Medicine and principal investigator of the study.
But the researchers still faced a hurdle before they could test their hypothesis about the role of oligomeric amyloid-beta, said one of her UIC coworkers.
"There are few methods for detecting the different aggregate forms of amyloid-beta," said Leon Tai, a research assistant professor working with LaDu. So, he said, the team developed a highly specific monoclonal antibody, which enabled them to assay only the specific oligomeric form of amyloid-beta.
This new monoclonal antibody, along with the new mouse model, "allowed us to identify the earliest accumulations of amyloid-beta and the differences related to the different forms of apoE," said LaDu.
The results were definitive: transgenic mice with apoE4 show an increase in the oligomeric form of amyloid-beta compared to mice carrying the other, more benign versions of apoE, providing a mechanism for apoE-induced Alzheimer's risk. Thus, previous transgenic mice lacking this interaction were poor models, say the researchers.
In addition, if oligomeric amyloid-beta is the cause of the disease, then it is also the earliest disease marker. Thus, the new model offers a clear picture of therapeutic effects on the cause of the disease not possible with the methods and models currently available.
"More than just an Alzheimer's risk factor, patients with apoE4 often respond differently to therapeutics in clinical trials, in many cases negatively," said Tai, whose background includes drug discovery. "However, preclinical compound testing in transgenic mouse models that express human apoE has not been possible until now."
"A pre-clinical model for testing these compounds has been badly needed, so we don't find ourselves in clinical trials with therapeutics that fail," said LaDu. She has begun collaborations with other researchers at UIC and worldwide to focus on drug discovery."We are actively working to test and develop novel compounds that we believe will benefit all Alzheimer's patients," she said.
Katherine Youmans, former UIC graduate student and now a postdoctoral researcher at Boston University, is first author of the paper. In addition to Youmans, Tai and LaDu, other authors are Evelyn Nwabuisi-Heath, Lisa Jungbauer and Chunjiang Yu from UIC; Takahisa Kanekiyo, Ming Gan and Guojun Bu of the Mayo Clinic in Jacksonville, Fla.; Jungsu Kim of Washington University School of Medicine; William Eimer of the Northwestern University Feinberg School of Medicine; G. William Rebeck of Georgetown University and Edwin Weeber of the University of South Florida.
Editor's Note: Images available at http://newsphoto.lib.uic.edu/v/LaDu/
Jeanne Galatzer-Levy | EurekAlert!
Portable finger-probe device can successfully measure liver function in potential organ donors
29.05.2015 | University of California - Los Angeles Health Sciences
Project start: New active substance targeting dreaded hospital pathogens
29.05.2015 | Deutsches Zentrum für Infektionsforschung
Many joining and cutting processes are possible only with lasers. New technologies make it possible to manufacture metal components with hollow structures that are significantly lighter and yet just as stable as solid components. In addition, lasers can be used to combine various lightweight construction materials and steels with each other. The Fraunhofer Institute for Laser Technology ILT in Aachen is presenting a range of such solutions at the LASER World of Photonics trade fair from June 22 to 25, 2015 in Munich, Germany, (Hall A3, Stand 121).
Lightweight construction materials are popular: aluminum is used in the bodywork of cars, for example, and aircraft fuselages already consist in large part of...
Nicht um Sonnenlicht geht es ihnen, sondern um Röntgenstrahlen: Wissenschaftler der Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) haben zusammen mit...
Mit ultrakurzen Laserpulsen haben Wissenschaftler aus dem Labor für Attosekundenphysik in dünnen dielektrischen Schichten EUV-Strahlung erzeugt und die zugrunde liegenden Mechanismen untersucht.
Das Jahr 1961, die Erfindung des Lasers lag erst kurz zurück, markierte den Beginn der nichtlinearen Optik und Photonik. Denn erstmals war es Wissenschaftlern...
Using ultrashort laser pulses, scientists in Max Planck Institute of Quantum Optics have demonstrated the emission of extreme ultraviolet radiation from thin dielectric films and have investigated the underlying mechanisms.
In 1961, only shortly after the invention of the first laser, scientists exposed silicon dioxide crystals (also known as quartz) to an intense ruby laser to...
Andy ist Physiker und wohnt in New York. Obwohl er schon seit fünf Jahren im Big Apple arbeitet, ist ihm die Stadt immer noch fremd – zu laut, zu hektisch, zu schmutzig. Wie soll das in Zukunft weitergehen? Die Antwort erfährt er prompt – und am eigenen Leib.
„New York – die Stadt, die niemals schläft.“ Lieber Franky Boy Sinatra, ich bin ganz bei Dir. Schon 1977 hattest du mit deinem Song ganz recht. Einen wichtigen...
29.05.2015 | Veranstaltungen
29.05.2015 | Veranstaltungen
28.05.2015 | Veranstaltungen