Improvised Alzheimer’s Mouse Model For Precision Medicine
Numerous Alzheimer’s disease associated pathology mimicking mouse models exist today. These models facilitate advanced research to study the disease in depth and it makes preclinical testings easier. But to date, no models replicate the human disease exactly which makes it difficult for the researchers to study it.
A group of researchers from Jackson Laboratory, US have developed a well-established mouse model of Alzheimer’s disease by the use of a genetically varied reference panel to create a mice model that displays identical human mutations but differ upon the rest of the genome. The use of genetic diversity resulted in greater overlap with the genetic, molecular, and clinical features of this pervasive human disorder.
This research was published in journal Neuron on Dec. 27 in a paper titled, “Harnessing Genetic Complexity to Increase Translatability of Alzheimer’s Disease Mouse Designs: A Course toward Precision Medicine”
NIA Director Richard J. Hodes, M.D said that this is the very first study to demonstrate the various molecular features of Alzheimer’s disease can be replicated in mouse models by focusing on genetic diversity factor. This discovery will lead to the use of these enhanced mouse models for precision medicine research.
Catherine Kaczorowski, Ph.D., associate professor in the Jackson Laboratory headed the research team. Together they developed an established mouse model of familial AD (5XFAD) using a genetically diverse group of mice. All members of the family of transgenic mice, therefore, take the high-risk human bronchial AD genes but otherwise have quite different genetic make-ups. The detailed analysis of the new panel of mice (referred collectively as AD-BXD), revealed a high degree of overlap with both molecular, molecular, pathologic, and cognitive features of AD. Moreover, in the presence of identical AD hazard genes, the differences in genetic history led to profound differences in the onset and severity of the cognitive and bronchial symptoms of AD.
During a series of comparative investigations, the study team also discovered a mouse strain, C57BL/6J, generally used to create AD transgenic mouse models, harbors resilience factors that reduce the impact of AD risk factor genes. To begin with, it suggests that AD mouse models with this genetic background might not be suitable for testing of novel therapeutic agents and might clarify the poor predictive ability of medication screening studies using the present AD transgenic mouse models. Secondly, using the AD-BXD panel, both the protective genes in the C57BL/6J strain and their mechanisms can be exactly identified contributing to new candidate targets for AD prevention.
The authors say that the AD-BXD panel reflects a brand new instrument for better understanding that the heterogeneous nature of aging and AD, and for precisely identifying molecular factors that lead to resilience to hereditary and environmental disease risk factors.
“The capability to simulate genetic predisposition and its impact on multiple facets of disease risk and durability in transgenic mice in a robust and reproducible way will allow the research community to find out a great deal more about the complex character of Alzheimer’s a lot faster,” says Suzana Petanceska, Ph.D., program manager in the NIA division of neuroscience, who manages the Resilience-AD application. “This new source increases the set of fresh NIA/NIH programs generating information, analytical, and research programs needed to enable more efficient and predictive drug development for Alzheimer’s.”
The researchers introduced a novel AD mouse population as an advanced and reproducible resource for the study of mechanisms underlying AD and gives proof that preclinical models incorporating genetic diversity may better interpret to human disease, increasing their usability for precision medication search for AD.
AD is an irreversible, progressive brain disease that gradually destroys thinking and memory skills and, eventually, the capacity to carry out simple tasks.
Dr. Kaczorowski’s team is one of 10 multidisciplinary and multi-institutional research teams supported via the Resilience-AD program, among a collection of NIA-supported open-science consortia. Resilience-AD, established in 2017, aims to address why and how a few individuals stay dementia-free despite being high genetic or biomarker risk of AD.