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New genetically modified mouse model mimics multiple aspects of human Alzheimer’s disease

NIA-supported scientists have developed a new mouse model that produces a form of the human beta-amyloid protein, a hallmark of Alzheimer’s disease. An important research tool, mouse models enable the exploration of genetic, environmental, and behavioral aspects of Alzheimer’s, as well as make it possible to test drug candidates before human studies. The new mouse model, which was reported in a recent article in Nature Communications, can be used by other scientists to advance Alzheimer’s research.

Abstract graphic of a brain with a silhouette of a mouse in the middle and dots and lines that represent brain connections.
Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD)

MODEL-AD consortium

Many factors, including gene changes, the aging process, and conditions in the environment, can promote the gradual development of Alzheimer’s. NIA invests in research to explore various disease-causing mechanisms and identify drug candidates that might prevent or delay the onset of Alzheimer’s.

As part of these investments, NIA established the Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) consortium to develop new animal models of late-onset Alzheimer’s, to characterize the models relative to multiple aspects of human disease, and to make all data and models available to researchers in academia and the biotechnology and pharmaceutical industries via the NIA-supported AD Knowledge Portal. To date, the MODEL-AD teams have generated more than 50 new mouse models.

New mouse model

An international team led by researchers at the University of California, Irvine, one of five MODEL-AD consortium institutions, set out to engineer a mouse model that could mimic the molecular pathways that lead to the late-onset, most common form of Alzheimer’s. This form does not have symptoms before about age 60 and occurs sporadically, rather than in several members of a family.

Most mouse models already being used to study Alzheimer’s were made to overexpress amyloid precursor protein. But these models are imperfect because the mice overproduce beta-amyloid in addition to other protein fragments.

The University of California, Irvine, research team had a different approach. The team slightly modified a mouse gene so that the mice could develop the human version of beta-amyloid protein. Then the team used the gene knock-in method to insert the modified gene at a specific location. The knock-in method helps scientists study the development of a disease and its effects on the body.

Next, the team analyzed the brains of the genetically modified mice and confirmed the presence of the human beta-amyloid. The protein was produced at normal levels, rather than overproduced, as in most other mouse models.

The team noted that the mice developed behavior changes and cognitive impairment as they grew old, like what occurs in many people with beta-amyloid plaques in their brain. The mice also had changes in gene expression that resembled patterns detected in the brains of people with Alzheimer’s. When the team blocked the modified gene so that the mice could not develop beta-amyloid, the mice did not develop age-related cognitive impairment.

This new mouse model with human beta-amyloid provides a novel way for researchers to study the aging, genetic, and environmental factors that promote Alzheimer’s. It can be used to introduce other Alzheimer’s risk and protective genetics factors and explore how genes and the environment are involved in the disease. In addition, researchers can use this mouse model to test the effectiveness of therapeutic agents.

The project was funded in part by NIA grants R01AG027544, P01AG000538, R21AG054884, U54AG054349, R01AG049562, R01AG056768, and P50AG016573.

These activities relate to NIH’s AD+ADRD Research Implementation Milestone 4.A, “Support the development of the next generation of animal models based on the current understanding of genetic and environmental risk and protective factors for AD and related dementias, using genome editing and other cutting edge technologies (optogenetics/deep brain stimulation/trans-magnetic stimulation, and next generation in vivo imaging) to facilitate assessment and validation of findings from human studies” and Milestone 4.B, “Create infrastructure/resources for extensive characterization of existing and new animal models and development of standardized and rigorous methods for preclinical efficacy testing including web-based resources for transparent reporting of both positive and negative findings.”

Reference: Baglietto-Vargas D, et al. Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology. Nature Communications. 2021;12(1):2421. doi: 10.1038/s41467-021-22624-z.