Astrocyte Dysfunction Causes Cognitive Decline | Writing

People with dementia have a buildup of proteins in astrocytes that can trigger abnormal antiviral activity and memory loss, according to a preclinical study by a team of researchers at Weill Cornell Medicine.

Dysfunction of cells called neurons, which transmit messages throughout the brain, has long been a prime suspect in dementia-related cognitive deficits. But a new study, published in Science Advances on April 19, suggests that abnormal immune activity in non-neuronal brain cells called astrocytes is sufficient to cause cognitive deficits in dementia. This discovery could lead to new treatments that reduce excess immune activity in astrocytes and its damaging effects on other brain cells and on cognition.

“Astrocyte dysfunction alone can lead to memory loss, even when neurons and other cells are otherwise healthy,” said the co-lead author. Dr. Anna Orr, Assistant Nan and Stephen Swid Professor of Frontotemporal Dementia Research at the Feil Family Brain and Mind Research Institute and Fellow of the Helen and Robert Appel Alzheimer’s Disease Research Institute in Weill Cornell Medicine. “We found, in mice, that astrocytes can cause cognitive decline through their antiviral activities, which can make neurons hyperactive.”

Dr. Anna Orr

While neurons have been studied intensively in dementia and other diseases, much less research has focused on astrocytes, which many scientists considered to play only a supporting role for neurons in the health of the brain. brain.

“We are very interested in the roles of astrocytes in cognitive and behavioral disorders,” she said. “These cells are widespread in the brain and perform a variety of key functions, but their involvement in neurocognitive disorders like dementia is poorly understood.”

When the researchers, including first author Dr. Avital Licht-Murava, a former postdoctoral associate in the Orr lab, examined tissue samples from deceased people who had been diagnosed with Alzheimer’s disease or frontotemporal dementia, they found an accumulation of a protein called TDP-43 in astrocytes in the hippocampus, a region of the brain crucial for memory. To understand the effects of this protein accumulation, the team conducted a series of experiments on mouse models and brain cells cultured in the laboratory. Other principal investigators who contributed to the study include Dr. Robert Schwartz at Weill Cornell Medicine and Dr. Robert Froemke at New York University.

In mice, the accumulation of TDP-43 in astrocytes was sufficient to cause progressive memory loss, but no other behavioral changes. “Hippocampal astrocytes appear to be more vulnerable to this pathology.” she says.

To understand the causes of memory loss at the molecular level, co-lead author Dr. Adam Orr, assistant professor of neuroscience research at the Feil Family Brain and Mind Research Institute and member of the Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine, analyzed gene expression and found high levels of antiviral gene activities, even though no virus was present in the brain. Astrocytes 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 found that levels of CXCR3 receptors were elevated in neurons in the hippocampus and that excessive activity of CXCR3 receptors made the neurons “overactive”, said Dr Anna Orr.

Dr. Adam Orr

“Blocking CXCR3 reduced neuronal firing in individual neurons, and knocking out CXCR3 in mice by genetic engineering attenuated cognitive deficits caused by astrocytic TDP-43 accumulation,” said Dr. Adam Orr. These experiments demonstrate that altered astrocytes may have a detrimental role in dementia, he said.

Both researchers were excited about the potential clinical implications of their findings.

“For effective therapeutics, 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. She 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 and increase individuals’ susceptibility to viral infections, which could further worsen brain health and promote some cases of dementia.

The team is currently investigating 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 susceptibility to disease in the brain,” said Dr. Anna Orr. “Understanding how they activate cognitive function or cause cognitive decline will be key to understanding brain health and developing effective therapies.”