Scientists at the UCI MODEL-AD group have developed a new mouse model that could help us understand Alzheimer’s disease better. The mouse model is called Trem2R47H NSS, and it has a genetic variant called TREM2 R47H that is one of the strongest known risk factors for developing late-onset Alzheimer’s in humans.
Previous Trem2R47H mouse models had a problem with “cryptic splicing,” which reduced the amount of protein produced by the gene. This made it difficult to study the effects of the genetic variant on the brain. The new UCI model overcomes this problem and produces the same amount of protein as the wild-type gene.
To study the effects of the genetic variant, the researchers treated the mice with a chemical called cuprizone that damages the protective covering around nerve cells in the brain. The new mouse model responded to the damage in the same way as wild-type mice, indicating that the genetic variant did not affect their ability to respond to brain damage.
The researchers also crossed the Trem2R47H NSS mice with a mouse model of Alzheimer’s called 5xFAD to see how the genetic variant affected the development of Alzheimer’s-like pathology in the brain. They found that at an early stage of the disease, the new mouse model had fewer and smaller microglia, which are immune cells that protect the brain from damage. These microglia also had trouble interacting with the plaques that form in the brains of Alzheimer’s patients. However, the researchers observed a suppressed inflammatory response and increased damage to nerve cells in these mice.
Interestingly, the new mouse model seemed to be protected from some of the synaptic damage caused by the 5xFAD mouse model. However, as the disease progressed, the new mouse model developed more severe symptoms, including deficits in synaptic function and increased inflammation.
This study provides a better understanding of how the TREM2 R47H genetic variant affects the brain in response to Alzheimer’s pathology. The researchers hope that this new mouse model will be useful for future studies of Alzheimer’s and could help identify new targets for treatment. The study was supported by the MODEL-AD consortium and several grants from the National Institutes of Health.
Read the full paper here.