Astrocyte dysfunction causes cognitive decline.newsroom

According to preclinical studies by a team of researchers at Weill Cornell Medicine, people with dementia have protein accumulation in their astrocytes that can cause abnormal antiviral activity and memory loss.

Dysfunction of cells called neurons, which carry messages throughout the brain, has long been a major cause of dementia-related cognitive impairment.but new studyPublished April 19 in Science Advances, the findings may lead to new treatments that reduce the excessive immune activity of astrocytes and their detrimental effects on other brain cells and cognition.

“Astrocyte dysfunction alone can cause memory loss even when neurons and other cells are healthy,” said the co-lead authors. Dr. Anna OrrHe is 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. “We found that in mice, astrocytes can cause cognitive decline and neuronal hyperactivity through antiviral activity.”

Dr. Anna Orr

Neurons have been intensively studied in dementia and other diseases, but little research has focused on astrocytes, which many scientists see only as supporting neurons in brain health. Very few.

“I am very interested in the role of astrocytes in cognitive and behavioral disorders,” she said. “These cells are ubiquitous in the brain and perform a variety of important functions, but their involvement in neurocognitive disorders such as dementia is poorly understood.”

Researchers, including first author Dr. Avital Licht-Murava, a former postdoctoral fellow in the Orr lab, examined tissue samples from deceased individuals diagnosed with either Alzheimer’s disease or frontotemporal dementia and found that TDP and An accumulation of a protein called 43 is located in astrocytes within the hippocampus, a brain region important for memory. To understand the effects of this protein accumulation, the research team performed a series of experiments in laboratory-grown mouse models and brain cells. Other senior researchers who contributed to this study include: Dr. Robert Schwartz at Weill Cornell Medicine Dr. Robert Fromke at New York University.

In mice, accumulation of TDP-43 in astrocytes was sufficient to cause progressive memory loss, but no other behavioral changes. It seems more vulnerable,” she said.

To understand the causes of amnesia at the molecular level, co-lead authors Dr. Adam OhAssistant 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. Astrocytes overproduce immune messengers called chemokines, which can activate the CXCR3 chemokine receptor normally found on infiltrating immune cells. Surprisingly, the research team found that CXCR3 receptor levels were elevated in hippocampal neurons, and that her excess CXCR3 receptor activity made the neurons “hyperactive,” said Dr. Anna Orr. .

Dr. Adam Oh

“Blocking CXCR3 reduced neuronal firing in individual neurons, and eliminating CXCR3 in mice by genetic engineering attenuated cognitive deficits caused by TDP-43 accumulation in 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.

“Astrocytes and neurons must be considered for effective therapy,” says Dr. Anna Orr.

Agents that target identified immune pathways may help improve cognitive function in people with dementia. She noted that scientists are already testing CXCR3 blockers in clinical trials to treat arthritis and other inflammatory conditions. may occur.

This study may also provide insight into how antiviral immune responses cause cognitive impairment. Previous studies have linked viral infections to Alzheimer’s disease and long-term neurocognitive effects such as memory loss and brain fog. Aberrant immune activity in astrocytes not only contributes to these cognitive effects, but may also increase an individual’s susceptibility to viral infections, further exacerbating brain health and promoting some cases of dementia. There is likely to be.

The team is currently studying how TDP-43 alters the antiviral activity of astrocytes and how these alterations increase the brain’s susceptibility to viral pathogens.

“Astrocytes may promote resilience or vulnerability to brain disease,” says Dr. Anna Orr. “To understand brain health and develop effective treatments, it is important to understand how they enable cognitive function or cause cognitive decline,” she said. ”