Breaking New Ground: Immune System Discovery Offers Potential Solution to Alzheimer’s

A groundbreaking study has shed new light on the relationship between the immune system and Alzheimer’s disease. Researchers at the University of Virginia School of Medicine have discovered that an immune molecule called STING plays a crucial role in driving the formation of amyloid plaques and tau tangles, hallmarks of Alzheimer’s.

The study found that blocking STING activity in lab mice protected them from mental decline, suggesting a promising new target for developing treatments. This breakthrough has far-reaching implications for understanding and treating not only Alzheimer’s but also other neurodegenerative diseases like Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and dementia.

“The findings demonstrate that the DNA damage that naturally accumulates during aging triggers STING-mediated brain inflammation and neuronal damage in Alzheimer’s disease,” said researcher John Lukens, PhD. “These results help to explain why aging is associated with increased Alzheimer’s risk and uncover a novel pathway to target in the treatment of neurodegenerative diseases.”

The study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, involved a team of researchers from UVA’s Department of Neuroscience and Center for Brain Immunology and Glia (BIG Center). They found that removing STING dampened microglial activation around amyloid plaques, protected nearby neurons from damage, and improved memory function in Alzheimer’s model mice.

The discovery of STING as a key player in the development of neurodegenerative diseases opens new doors for research into potential treatments. While much more work is needed to translate these findings into effective therapies, this breakthrough has sparked hope among researchers and patients alike.

“Our hope is that this work moves us close to finding safer and more effective ways to protect the aging brain,” said Lukens. “Shedding light on how STING contributes to that damage may help us target similar molecules and ultimately develop effective disease-modifying treatments.”

Research has discovered that men who carry a common genetic variant are twice as likely to develop dementia in their lifetime compared to women. This groundbreaking study, published in Neurology, used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether people with variants in the haemochromatosis (HFE) gene might be at increased risk of dementia.

One in three people carry one copy of the H63D variant, while one in 36 carry two copies. Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia. However, having two copies of the variant more than doubled the risk of dementia in men, but not women.

The researchers emphasize that the genetic variant itself cannot be changed, but the brain pathways affected by it could potentially be treated if we understood more about it. Further research is needed to investigate why this genetic variant increased the risk of dementia for males but not females.

The findings suggest that perhaps testing for the HFE gene could be offered to men more broadly, considering its routine testing in most Western countries, including Australia, when assessing people for haemochromatosis – a disorder that causes the body to absorb too much iron. The study found no direct link between iron levels in the blood and increased dementia risk in affected men.

This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body. Understanding why men with the double H63D variant are at higher risk could pave the way for more personalized approaches to prevention and treatment.

The ASPREE trial was a groundbreaking study that created a treasure trove of healthy ageing data, which has underpinned a wealth of research studies. This collaboration between Curtin University, Monash University, The University of Melbourne, The Royal Children’s Hospital, Murdoch Children’s Research Institute, and Fiona Stanley Hospital demonstrates the importance of diverse Australian research groups working together to improve health outcomes for people around the world.

The implications of this study are significant, considering that more than 400,000 Australians are currently living with dementia, with around a third of those being men. This discovery could lead to improved outcomes for people at risk of developing dementia and ultimately contribute to a better understanding of these progressive diseases.

The Broad Institute has made a groundbreaking discovery in treating Huntington’s disease and Friedreich’s ataxia by developing a novel approach to edit the genetic sequences responsible for these conditions. These severe neurological disorders are caused by repeated three-letter stretches of DNA that grow uncontrollably, leading to brain cell death or nerve fiber breakdown. The researchers have successfully disrupted this repeat sequence using base editing, a technique that introduces single-letter changes into the middle of the repeated stretch of DNA.

The study, published in Nature Genetics, was led by David Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad. The research team included postdoctoral researcher Mandana Arbab, graduate student Zaneta Matuszek, and associate scientist Ricardo Mouro Pinto.

The breakthrough comes from the realization that some individuals with the same disease can inherit different numbers of DNA repeats, with more repeats generally leading to faster symptom progression. However, patients who have naturally occurring single-letter interruptions within these repeats often experience milder symptoms and are less likely to pass their disease along to their children. This observation inspired the researchers to develop a gene-editing therapy that could install an interruption mimicking those that occur naturally.

Using base editing, developed by Liu’s lab in 2016 for making single-letter changes in DNA, the team introduced interruptions into the repeat sequences of patient cells and mouse models of Huntington’s disease and Friedreich’s ataxia. The results showed that the edited DNA tracts stayed the same or even became shorter over time.

The researchers caution that more work is needed to catalog potential side effects of installing these edits in the genome, but the approach could be a valuable tool for understanding diseases caused by repeated three-letter sequences. “A lot more studies would be needed before we can know if disrupting these repeats with a base editor could be a viable therapeutic strategy to treat patients,” said Liu.

The team’s findings suggest that this gene-editing therapy could help treat Huntington’s, Friedreich’s ataxia, and other trinucleotide repeat disorders. “Not only does this study show for the first time that inducing interruptions has a profound stabilizing effect on repeats, but that the base-editing approach we’ve used can also be applied to study any of over a dozen repeat disorders,” said Arbab.

The research was supported by various organizations, including the Chan Zuckerberg Initiative, Lodish Family Foundation, National Institutes of Health, and Howard Hughes Medical Institute. The team is now developing a different approach using prime editing to replace disease-causing repeat tracts with a shorter, stable number of repeats all at once.