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!
Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine
Flexible sensors can detect movement in GI tract
11.10.2017 | Massachusetts Institute of Technology
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
It's possible to produce hydrogen to power fuel cells by extracting the gas from seawater, but the electricity required to do it makes the process costly. UCF...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
17.10.2017 | Life Sciences
17.10.2017 | Physics and Astronomy
17.10.2017 | Life Sciences