People with dementia have a buildup of proteins in their astrocytes that can trigger abnormal antiviral activity and memory loss, according to a preclinical study by a team of Weill Cornell Medicine researchers.
Dysfunction in cells called neurons, which carry messages throughout the brain, has long been a prime suspect in dementia-related cognitive deficits. But a new study, published in Progress of science on April 19, suggests that abnormal immune activity in non-neuronal brain cells called astrocytes is sufficient to cause cognitive deficits in dementia. The discovery could lead to new treatments that reduce excess immune activity in astrocytes and its detrimental effects on other brain cells and cognition.
“Astrocyte dysfunction alone can lead to memory loss, even when neurons and other cells are healthy,” said co-senior author Dr. Anna Orr, the Nan and Stephen Swid Assistant Professor of Dementia Research. frontotemporal 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. “We found, in mice, that astrocytes can cause cognitive decline through their antiviral activities, which can cause neurons to become hyperactive.”
While neurons have been intensively studied in dementia and other diseases, much less research has focused on astrocytes, which many scientists thought only played supportive roles for neurons in brain health.
“We are very interested in the roles of astrocytes in cognitive and behavioral disorders,” he said. “These cells are prevalent in the brain and perform several key functions, but their role in neurocognitive disorders such as dementia is not well understood.”
When the researchers, including first author Dr. Avital Licht-Murava, a former postdoctoral associate in Orr’s lab, examined tissue samples from deceased people diagnosed with Alzheimer’s disease or frontotemporal dementia, they found a accumulation of a protein called TDP-43 in astrocytes within the hippocampus, a region of the brain crucial for memory. To understand the effects of this protein buildup, the team conducted a series of experiments on mouse models and brain cells grown in the lab. Other principal investigators who contributed to the study include Dr. Robert Schwartz of Weill Cornell Medicine and Dr. Robert Froemke of New York University.
In mice, the accumulation of TDP-43 in astrocytes was sufficient to cause progressive memory loss, but not other behavioral changes. “Astrocytes in the hippocampus appear to be most vulnerable to this pathology.” she said.
To understand the causes of memory loss at the molecular level, co-senior author Dr. Adam Orr, a research assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute and a member of the Research Institute of Alzheimer’s Disease Appel at Weill Cornell Medicine, analyzed gene expression and found high levels of antiviral gene activity, even though no virus was present in the brain. The astrocytes produced excessive amounts of immune messengers called chemokines, which can activate CXCR3 chemokine receptors normally found on infiltrating immune cells. To their surprise, the team found that CXCR3 receptor levels were elevated in hippocampal neurons, and that excessive CXCR3 receptor activity made the neurons “hyperactive,” said Dr. Anna Orr.
“Blockade of CXCR3 reduced neuronal firing in individual neurons, and knockdown of CXCR3 in mice by genetic engineering alleviated cognitive deficits caused by accumulation of TDP-43 astrocytes,” said Dr. Adam Orr. These experiments show that impaired astrocytes may play a detrimental role in dementia, he said.
Both researchers were excited about the potential clinical implications of their findings.
“For effective therapy, we need to consider astrocytes along with neurons,” said Dr. Anna Orr.
Drugs that target identified immune pathways could help improve cognitive function in people with dementia. He noted that scientists are already testing CXCR3 blockers to treat arthritis and other inflammatory conditions in clinical trials. These drugs could be tested and potentially repurposed for dementia.
This study may also provide insight into how antiviral immune responses can cause cognitive dysfunction. Previous research has linked viral infections to Alzheimer’s disease and long-term neurocognitive effects such as memory loss and brain fog. Abnormal immune activity in astrocytes could contribute to these cognitive effects, as well as increase people’s susceptibility to viral infections, which could further worsen brain health and promote some cases of dementia.
The team is currently studying how TDP-43 alters antiviral activities in astrocytes and whether these changes increase the brain’s susceptibility to viral pathogens.
“Astrocytes may promote resilience or vulnerability to brain disease,” said Dr. Anna Orr. “Understanding how they enable cognitive function or cause cognitive decline will be critical to understanding brain health and developing effective therapies.”