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2021 AD Strategic Fund: Neuroimmune (ADSF)

AIMing at DNA damage sensors to take the STING out of Alzheimer’s disease

How may damage to a person’s DNA (genetic material) impact brain changes observed in Alzheimer’s?

John Lukens, Ph.D.
University of Virginia
Charlottesville, VA - United States


Past studies show that a buildup of DNA (an individual’s genetic material) damage has been implicated in several brain diseases including Alzheimer’s. Studies also indicate that buildup of DNA damage in the brain may be associated with brain inflammation and loss of nerve cells in the brain. 

The immune system is complex and serves to maintain our overall health. In our brain, the immune system specifically serves to maintain healthy nerve cells. Individuals with Alzheimer’s typically experience brain inflammation caused by dysregulation of the immune system, which may damage nerve cells. Scientists are trying to understand the biological mechanisms by which the buildup of DNA damage may be associated with brain changes, including brain inflammation observed in Alzheimer’s. 

Recent studies have found that DNA damage may activate certain biological pathways in the immune system. In particular, the immune system specific “sensors”, called AIM2 inflammasome and cGAS-STING, detect DNA damage and have also been shown to repair this damage. In addition, these sensors have been shown to activate other proteins associated with brain inflammation and subsequent loss of nerve cells in individuals with Alzheimer’s.

Research Plan

Dr. John Lukens and colleagues will investigate how the dysfunction in the sensors involved in DNA repair may impact the development and progression of Alzheimer’s. The researchers will use two types of mouse models that have been genetically engineered- (1) to develop Alzheimer’s-like brain changes and (2) to lack either AIM2 inflammasome or cGAS-STING. Dr. Lukens’ team will then perform behavioral experiments and compare how the different mouse models perform on tests of memory.

Further, using brain tissue from these mice, the researchers will study whether the inclusion or lack of these sensors impacts different biological markers of Alzheimer’s–such as levels of proteins associated with brain inflammation as well as levels of beta-amyloid and loss of nerve cells.


The study results could provide insights into how damage to the DNA may impact the role of immune system in Alzheimer’s and other brain diseases. The findings may also identify potential novel targets for future therapies for Alzheimer’s.

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

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