A team of Weill Cornell Medicine investigators found that individuals with dementia exhibit protein accumulation in astrocytes, which could initiate unusual antiviral activity and cognitive decline, as per a preclinical investigation.

For a long time, cognitive impairments related to dementia were attributed to malfunctioning neurons that facilitate communication within the brain. However, a recent study, published on April 19 in Science Advances, proposes that unusual immune activity in non-neuronal brain cells, known as astrocytes, can solely lead to cognitive deficits in dementia. This finding may pave the way for novel therapies that target the surplus immune activity in astrocytes, and subsequently mitigate their destructive impact on cognition and other brain cells.

Dr. Anna Orr, the Nan and Stephen Swid Assistant Professor of Frontotemporal Dementia Research at the Feil Family Brain and Mind Research Institute and a member of the Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell Medicine, and co-senior author of the study stated that "Memory loss can be attributed to astrocyte dysfunction alone, despite the overall health of neurons and other cells." She added that their research, conducted in mice, demonstrated that astrocytes' antiviral activity could cause cognitive decline by inducing hyperactivity in neurons.

Neurons have been extensively examined in dementia and other illnesses, whereas astrocytes have received far less attention. Until recently, many scientists believed that astrocytes solely played a supportive role in maintaining brain health, and their contributions to cognitive function were insignificant.

"We are highly intrigued by the functions of astrocytes in cognitive and behavioral disorders," Dr. Orr commented. "These cells are widespread in the brain and play a crucial role in several functions. However, their contribution to neurocognitive disorders, such as dementia, remains poorly comprehended."

The team's experiments on mice demonstrated that the accumulation of TDP-43 protein in astrocytes alone was adequate to cause a gradual loss of memory, without any noticeable behavioral modifications. "Astrocytes located in the hippocampus appear to be more susceptible to this pathology," Dr. Orr explained.

To gain insight into the molecular mechanisms underlying memory loss, co-senior author Dr. Adam Orr, an assistant professor of research in neuroscience in the Feil Family Brain and Mind Research Institute and a member of the Appel Alzheimer's Disease Research Institute at Weill Cornell Medicine, examined gene expression levels. Despite the absence of any virus in the brain, he discovered high levels of antiviral gene activities. Astrocytes produced an excess of immune messengers known as chemokines, which stimulated CXCR3 chemokine receptors, typically found on infiltrating immune cells. To their surprise, the research team discovered that hippocampal neurons had increased levels of CXCR3 receptors, and that excessive CXCR3 receptor activity caused neurons to become "hyperactive," according to Dr. Anna Orr.

Dr. Adam Orr stated that "Inhibiting CXCR3 resulted in a decrease in neuronal firing in individual neurons, and the elimination of CXCR3 in mice through genetic engineering relieved the cognitive deficits induced by astrocytic TDP-43 accumulation." These findings indicate that dysfunctional astrocytes may have a harmful effect on dementia, he added.

Both investigators were excited by the potential clinical implications of their findings.

“For effective therapeutics, we need to consider astrocytes along with neurons,” Dr. Anna Orr said.

According to Dr. Anna Orr, drugs that target the immune pathways identified in their study may aid in the improvement of cognitive function in individuals with dementia. She mentioned that CXCR3 blockers are already being tested in clinical trials to treat inflammatory conditions such as arthritis. These medications could potentially be repurposed and tested to treat dementia.

This research could also offer insights into how antiviral immune responses could result in cognitive impairment. Previous studies have linked viral infections to Alzheimer's disease and long-term neurocognitive effects such as memory loss and brain fog. Abnormal immune activity in astrocytes may play a role in these cognitive effects, as well as increase an individual's vulnerability to viral infections, which could further impair brain health and contribute to certain forms of dementia.

The researchers are currently investigating how TDP-43 modifies antiviral activities in astrocytes and if these changes lead to an increased vulnerability of the brain to viral pathogens.

Dr. Anna Orr emphasizes that astrocytes can either promote resilience or vulnerability to brain diseases. Therefore, comprehending how these cells can either enable cognitive function or cause cognitive decline is crucial for developing effective therapies and advancing our understanding of brain health. (PB/Newswise)