A new way of thinking about Alzheimer’s disease has led to a discovery that could be the key to halting cognitive decline in Alzheimer’s and other neurodegenerative diseases. Scientists at the University of Virginia School of Medicine have been investigating the possibility that Alzheimer’s is caused, at least in part, by the immune system’s misguided attempts to repair DNA damage in the brain. Their research shows that an immune molecule called STING drives the formation of the damaging plaques and protein clumps blamed for Alzheimer’s. By blocking the molecule, laboratory mice could be protected from mental decline, according to the researchers.
How Removing STING Can Protect the Brain
STING plays an important role in the brain’s immune system and may also be instrumental in the development of Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s syndrome), dementia and other diseases that lead to memory loss. This means that the development of therapies to control its activity could have far-reaching benefits for many patients currently facing a devastating diagnosis.
“Our results show that the DNA damage that naturally accumulates during the aging process triggers STING-mediated brain inflammation and neuronal damage in Alzheimer’s disease,” said researcher John Lukens, PhD, director of the Harrison Family Translational Research Center for Alzheimer’s and Neurodegenerative Diseases at UVA. “These findings help explain why age is associated with an increased risk of Alzheimer’s and open up a new approach to treating neurodegenerative diseases.”
Alzheimer’s is a growing problem, with the number of cases rising steadily. By 2050, around 153 million people could suffer from dementia. Researchers are therefore working feverishly to find ways to better understand and treat the disease. The causes of Alzheimer’s remain unclear, but scientists are increasingly recognizing the role of the immune system in the development of the disease. STING is part of this immune response; the molecule helps to eliminate viruses and stressed cells with DNA damage.
While STING is an important defender of the brain, it can also become hyperactive and cause harmful inflammation and tissue damage. This prompted Lukens and his team to find out what role it might play in Alzheimer’s disease. They found that blocking the activity of the molecule in laboratory mice helped to prevent the formation of Alzheimer’s plaques, alter the activity of immune cells called microglia, and redirect the function of important genes, among other things.
“We found that removing STING dampened the activation of microglia around amyloid plaques, protected neighboring neurons from damage, and improved memory function in Alzheimer’s model mice,” said researcher Jessica Thanos of UVA’s Department of Neuroscience and Center for Brain Immunology and Glia (BIG Center). Taken together, these results suggest that STING triggers harmful immune responses in the brain that exacerbate neuronal damage and contribute to cognitive decline in Alzheimer’s disease.
Developing Effective Treatments for Alzheimer’s Disease
While scientists are studying other molecules thought to be important in Alzheimer’s disease, the UVA Health researchers say STING is a particularly attractive target for the development of new therapies. This is because blocking STING appears to slow both the formation of amyloid plaques and the development of tau clumps, the two prime suspects in the development of Alzheimer’s disease. Other molecules do not show such a strong involvement and could only be targeted at very specific – and very limited – stages of the disease progression.
“We are only just beginning to understand the complex role of innate immune activation in the brain, and this is particularly true in normal and pathological ageing,” says Thanos. “If we can determine exactly which cells and signals maintain this activation, we will be in a much better position to effectively intervene in disease progression.” While Lukens’ groundbreaking research has opened new doors in the fight against Alzheimer’s, much more needs to be done to translate the findings into treatments. For example, scientists need to better understand the role of STING in the body – for example in the immune system’s response to cancer – to ensure that new treatments do not have unwanted side effects.
But these are the big questions that Lukens and his colleagues at the Harrison Family Translational Research Center want to address as part of their efforts to rapidly develop new therapies, and ultimately, they hope, find cures. The researchers hope this work will bring them closer to discovering safer and more effective ways to protect the aging brain, as treatments that can slow or prevent neuronal damage in Alzheimer’s are urgently needed. By gaining insight into how STING contributes to this damage, they may be able to identify similar molecules and ultimately develop effective disease-modifying treatments.