<< Back

2021 AD Strategic Fund: Neuroimmune (ADSF)

Deciphering Microglial Responses to Amyloid and Tau with Wild-Derived Mice

Could new mouse models improve the understanding of immune cell responses in Alzheimer’s?

Gareth Howell, Ph.D.
The Jackson Laboratory
Bar Harbor, ME - United States


Microglia are immune cells that serve as one of the brain’s first defenses against nerve cell damage. Microglia sense and help remove proteins that can accumulate in the brain during Alzheimer’s and other brain diseases and that may contribute to some of the nerve cell damage in these diseases. When activated, microglia release molecules that help bring other immune cells to the site of damage. In Alzheimer’s, past research has suggested that microglia become overactivated, which can cause inflammation in the brain that may also damage nerve cells. 

Recent advances in biological techniques have shown that microglia exhibit a wide variety of responses depending on age, disease and type of injury, among others. Since they are grown in the laboratory and may not capture the diverse microglial responses that are observed in humans, current mouse models may not fully represent the brain changes observed in Alzheimer’s in humans. In preliminary results, using genetically engineered Alzheimer’s-like mouse models, Dr. Gareth Howell’s team found that microglial responses depend upon on the genetic makeup of these mice. 

To better capture the diversity of microglial responses as seen in humans, Dr. Howell’s team used natural variety of mice (called “wild-derived”) and genetically engineered these mice to have Alzheimer’s-like brain changes. Preliminary results from Dr. Howell and colleagues found that the wild-derived mouse models showed varied microglial responses when exposed to high levels of beta-amyloid (a protein that accumulates in a hallmark brain change in Alzheimer’s).

Research Plan

Using the wild-derived mice to replicate human brain changes observed in Alzheimer’s, the researchers will genetically engineer these models to have both human beta-amyloid and human tau protein. Beta-amyloid and tau accumulate in the brain to form plaques and tangles respectively, two of the hallmark brain changes observed in Alzheimer’s. The research team will then study the microglial responses to the brain changes in these mice. Additionally, the researchers will conduct behavioral experiments to study cognition in these mice. 
The researchers will also use genetic analyses to understand how differences in microglia responses may impact disease progression. To help validate their model and findings, the researchers will compare their genetic analyses to studies performed on brain tissue from individuals with Alzheimer’s. Dr. Howell believes that the study findings may pave the way for the development of microglia-based therapies to prevent the progression of Alzheimer’s and other dementia.


This study will generate a mouse model of Alzheimer’s that may better represent diverse genetic factors and biological processes associated with Alzheimer’s in humans. This model will be shared broadly and be made available to a wider research community. This study may also uncover genes related to microglia responses in the brain that may be associated with the progression of Alzheimer’s.

Made possible through the generous funding from an Anonymous Foundation and the Alzheimer’s Association.

Back to Top