Researchers are currently striving to produce the first type of mice that are genetically prone to late-onset Alzheimer’s, a breakthrough that could have a considerable impact on dementia studies.
Mice typically do not exhibit symptoms of Alzheimer’s; while this is beneficial for mice, it poses a significant challenge for scientists studying the disease and testing potential treatments. At The Jackson Laboratory, researchers are diligently working on creating a strain of mice genetically predisposed to late-onset Alzheimer’s, which could revolutionize dementia research.
In humans, two primary characteristics of Alzheimer’s disease are the presence of amyloid plaques between brain cells and tangles of tau proteins inside neurons. However, mice do not exhibit the same cognitive impairments because the plaques between their cells do not lead to protein tangles within neurons. Greg Carter, the Bernard and Lusia Milch Endowed Chair at JAX, along with JAX colleagues Gareth Howell, Ph.D., and Mike Sasner, Ph.D., mentioned, “It is relatively simple to create mouse models that focus on studying amyloid plaques; however, this only captures a small aspect of Alzheimer’s. If curing the disease were possible using these models, it would have been accomplished 20 years ago.”
To create new strains of mice that accurately reflect the complexity of Alzheimer’s disease, Carter’s team referred to recent genome-wide studies identifying over 70 genes linked to the illness. Through CRISPR gene editing, they, in collaboration with Sasner and Howell, introduced various genetic factors associated with Alzheimer’s into 11 distinct strains of mice. These mice were then raised to maturity to explore how the genetic variations influenced their brain health.
Identifying the onset of Alzheimer’s in mice posed a challenge as it is arduous to gauge the impact of the disease on their cognitive abilities due to their limited cognitive capacity. To address this, the JAX team employed transcriptomics, a technique that reveals how genes are transcribed and activated within cells. By comparing the biological signatures in mouse brains with those of deceased human Alzheimer’s patients, Carter explained, “By examining the molecular biology of both mouse and human brains, we can identify commonalities and isolate the Alzheimer’s disease biology driven by a specific gene.”
Furthermore, using transcriptomics provides a clearer foundation for testing new treatments. For instance, if a therapy aims to counter inflammation linked to Alzheimer’s, its effect on the inflammation-associated transcriptome signature can be evaluated. Carter stated, “This method allows for assessing the efficacy of a treatment at a molecular level without the need to rely solely on behavioral changes that are challenging to detect in mice. It enhances precision and efficiency in preclinical studies.”
Prior to combining the genes into a single mouse strain exhibiting all key Alzheimer’s biological characteristics, Carter and his team must first determine the individual contributions of each genetic factor. Another project involved testing approximately a dozen additional genes to identify the most effective way to amalgamate them into a single mouse model. Carter explained, “Through machine learning, we have determined the optimal gene combinations. We are now conducting studies to combine three or four genes at a time, with the aim of producing mice exhibiting a more comprehensive Alzheimer’s model.”
This ambitious endeavor is crucial as most mouse-model research on dementia focuses on the impact of individual genes. Carter clarified, “While certain genes may raise the risk of dementia, Alzheimer’s is not caused by a single gene as it involves complex genetics.” Working at JAX has facilitated the examination of numerous genes simultaneously and the identification of an ideal model for Alzheimer’s disease research,” Carter emphasized.
“Having a mouse model for Alzheimer’s disease would be invaluable,” Carter commented. “This research is bringing us one step closer to achieving that objective.”
