Researchers at the University of Illinois at Chicago College of Medicine have developed a transgenic mouse that carries a human gene known to increase risk of Alzheimer's 15-fold. This new mouse model is a cross between an existing transgenic Alzheimer's mouse and a mouse carrying the full length copy of human apoE4. Earlier work has identified apoE4, as the greatest genetic risk factor for Alzheimer's in the human population. The new mouse model 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 original report will be published in the December issue of the Journal of Biological Chemistry.
UIC biochemist Mary Jo LaDu, Ph.D., 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 Dr. LaDu, associate professor of anatomy and cell biology at the UIC College of Medicine and principal investigator of the study.
There is one last hurdle: "There are few methods for detecting the different aggregate forms of amyloid-beta," said Leon Tai, the research assistant professor working with LaDu. “The team developed a highly specific monoclonal antibody, which enabled us to assay only the specific oligomeric form of amyloid-beta we're interested in.”
Continued Dr LaDu, “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."
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, it would appear that previous transgenic mice lacking this interaction were poor models.
Further, the work suggests that if oligomeric amyloid-beta is the cause of the disease, then it is also the earliest disease marker. Thus, the new model could offer a clearer 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 Dr. Tai. "However, preclinical compound testing in transgenic mouse models that express human apoE has not been possible until now."
"A preclinical model for testing these compounds has been badly needed, so we don't find ourselves in clinical trials with therapeutics that fail," said Dr. LaDu. "We are actively working to test and develop novel compounds that we believe will benefit all Alzheimer's patients."
The researchers at UIC have begun collaborations with other researchers at UIC and worldwide to focus on drug discovery.