Astrocyte dysfunction causes cognitive decline, new research shows

Non-neuronal brain cells could be an overlooked culprit of memory loss – a discover that could signpost the way to potential dementia therapies.

Dementia is a neurodegenerative disease that affects millions of people worldwide, causing memory loss and cognitive decline. While the dysfunction of neurons has long been considered the primary cause of dementia-related cognitive deficits, a new study published in Science Advances reveals that non-neuronal brain cells, called astrocytes, may play a significant role in the disease.

Longevity.Technology: Alzheimer’s disease is a pernicious threat to global health and longevity, affecting millions of people worldwide and their families. With an aging population, the prevalence of dementia is projected to increase dramatically in the coming decades, placing an enormous burden on healthcare systems and societies. Despite decades of research, there are still no effective treatments that can slow or stop the progression of the disease.

The urgent need for effective treatments that can alleviate the cognitive deficits and other debilitating symptoms of Alzheimer’s disease cannot be overstated; the findings of this study provide new insights into the role of astrocytes in dementia and suggest a promising avenue for the development of therapies that could improve cognitive function in people with Alzheimer’s and other forms of dementia.

According to the preclinical study, people with dementia have protein build-up in astrocytes that may trigger abnormal antiviral activity and memory loss. These findings could lead to new treatments that reduce excess immune activity in astrocytes and their detrimental effects on other brain cells and cognition [1].

“Astrocyte dysfunction alone can drive memory loss, even when neurons and other cells are otherwise healthy,” says Dr Anna Orr, a member of the Alzheimer’s Disease Research Institute at Weill Cornell Medicine [2].

The team of investigators, which included Dr Avital Licht-Murava, a former postdoctoral associate in the Orr lab, found an accumulation of a protein called TDP-43 in astrocytes within the hippocampus, a brain region crucial for memory, when examining tissue samples from deceased individuals who were diagnosed with either Alzheimer’s disease or frontotemporal dementia.

To understand the effects of this protein build-up, the team conducted a series of experiments in mouse models and brain cells grown in the laboratory. They found that the build-up of TDP-43 in astrocytes was sufficient to cause progressive memory loss but not other behavioral changes [1].

To understand the causes of memory loss at the molecular level, Dr Adam Orr, an assistant professor of research in neuroscience at Weill Cornell Medicine, analyzed gene expression and found high levels of antiviral gene activities, even though no virus was present in the brain.

The astrocytes in the study produced excessive amounts of immune messengers called chemokines, which can activate CXCR3 chemokine receptors typically found on infiltrating immune cells. To their surprise, the team discovered that CXCR3 receptor levels were elevated in hippocampal neurons, and that excessive CXCR3 receptor activity made neurons “hyperactive.” This activity ultimately contributes to memory loss [1].

“Blocking CXCR3 reduced neuronal firing in individual neurons, and eliminating CXCR3 in mice by genetic engineering alleviated cognitive deficits caused by astrocytic TDP-43 build-up,” Dr Adam Orr said [2].

Drugs that target the identified immune pathways might help improve cognitive function in people with dementia. Scientists are already testing CXCR3 blockers to treat arthritis and other inflammatory conditions in clinical trials – these drugs could potentially be repurposed for dementia.

The study may also provide insights into how antiviral immune responses can cause cognitive dysfunction. Previous research has linked viral infections to Alzheimer’s disease and to long-term neurocognitive effects such as memory loss and brain fog.

The team is currently studying how TDP-43 alters antiviral activities in astrocytes and whether these changes increase brain susceptibility to viral pathogens.

“Astrocytes can promote resilience or vulnerability to brain disease,” Dr Anna Orr said. “Understanding how they enable cognitive function or cause cognitive decline will be critical to understanding brain health and developing effective therapies [2].”

Overall, the findings of this study highlight the importance of studying non-neuronal brain cells and their potential contribution to cognitive decline in dementia; by understanding how astrocytes play a role in the disease, scientists may be able to develop new treatments that can alleviate cognitive deficits and improve brain health.