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2016 Grants - Cynis
Generation and Characterization of Novel APP-wt x Tau-wt Double Knock-In Mice
Holger Cynis, Ph.D.
2016 New Investigator Research Grant
Can mouse models of Alzheimer’s disease be improved to more accurately represent human disease?
Many researchers study Alzheimer’s-like mice to better understand the fundamental mechanisms of the disease. Since mice do not naturally develop Alzheimer’s disease, the mice used for research studies are genetically modified to produce the disease-like characteristics observed in humans. Some Alzheimer’s-like mice have been modified to have high levels of human genes known to be associated with Alzheimer’s disease. While this helps researchers uncover new and valuable information, the “overexpression” of these genes can lead to brain changes unrelated to the disease process. These side effects can limit the usefulness of the animal models and make it difficult to translate the findings to humans.
Two genes found in humans and relevant to Alzheimer’s disease are amyloid precursor protein (APP) and Tau. These genes are normally involved in the production of naturally occurring beta-amyloid protein and tau proteins. In Alzheimer’s disease these proteins can abnormally clump in the brain and accumulate into plaques and tangles – the two hallmarks of the disease. Currently available research mice have forms of these genes which may not accurately make the types of beta-amyloid and tau proteins actually found in the brains of people with Alzheimer’s disease.
Holger Cynis, Ph.D. and colleagues are working to develop Alzheimer’s-like mice that carry the genes to make the same types and amounts of beta-amyloid and tau proteins that are found in humans. The researchers will create these new Alzheimer’s-like mice by deleting the mouse APP and Tau genes and replacing them with the human versions. The goal is for these genetically modified mice to more accurately reflect the brain changes seen in people with Alzheimer’s disease. The researchers will analyze cognition and brain tissue from these mice at different ages to determine if they develop Alzheimer’s disease similar to that observed in the human brain.
The mice developed in this study may serve as more accurate models of Alzheimer’s disease than other available research mice. Animal models that precisely reflect the brain changes associated with Alzheimer’s disease are critical to the initial phases of drug testing. The goal of this project is to support the advancement of diagnostics and potential drug treatments from animals to humans, which has been a significant challenge for Alzheimer’s research.