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!
Real-time imaging of lung lesions during surgery helps localize tumors and improve precision
30.07.2015 | American Association for Thoracic Surgery
Experimental MERS vaccine shows promise in animal studies
29.07.2015 | NIH/National Institute of Allergy and Infectious Diseases
Verdichterscheiben für Flugzeugturbinen werden aus einem Materialstück herausgefräst. Bei der Bearbeitung fangen die Schaufeln an zu schwingen. Ein neuartiges Spannsystem steigert die Dämpfung der Schaufeln nun auf mehr als das 400-fache. Es lassen sich bis zu 5000 Euro Kosten bei der Fertigung einsparen.
Mal eben schnell in den Urlaub jetten oder für ein langes Wochenende nach Rom, Paris oder Madrid fliegen? Der Flugverkehr steigt, insbesondere der...
Der Gletscherschwund im ersten Jahrzehnt des 21. Jahrhunderts erreicht einen historischen Rekordwert seit Messbeginn. Das Schmelzen der Gletscher ist ein globales Phänomen und selbst ohne weiteren Klimawandel werden sie zusätzlich an Eis verlieren. Dies belegt die neueste Studie des World Glacier Monitoring Services unter der Leitung der Universität Zürich.
Seit über 120 Jahren sammelt der World Glacier Monitoring Service, mit heutigem Sitz an der Universität Zürich, weltweite Daten zu Gletscherveränderungen....
Glacier decline in the first decade of the 21st century has reached a historical record, since the onset of direct observations. Glacier melt is a global phenomenon and will continue even without further climate change. This is shown in the latest study by the World Glacier Monitoring Service under the lead of the University of Zurich, Switzerland.
The World Glacier Monitoring Service, domiciled at the University of Zurich, has compiled worldwide data on glacier changes for more than 120 years. Together...
Mit ultrakalten Atomen lässt sich ein neuer Materiezustand beobachten, in dem das System nicht ins thermische Gleichgewicht kommt.
Was passiert, wenn man kaltes und heißes Wasser mischt? Nach einer Weile ist das Wasser lauwarm – das System hat ein neues thermisches Gleichgewicht erreicht....
Using ultracold atoms trapped in light crystals, scientists from the MPQ, LMU, and the Weizmann Institute observe a novel state of matter that never thermalizes.
What happens if one mixes cold and hot water? After some initial dynamics, one is left with lukewarm water—the system has thermalized to a new thermal...
03.08.2015 | Veranstaltungen
03.08.2015 | Veranstaltungen
31.07.2015 | Veranstaltungen
03.08.2015 | Veranstaltungsnachrichten
03.08.2015 | Seminare Workshops
03.08.2015 | Seminare Workshops