Cognitive decline may be triggered by astrocyte dysfunction – Neuroscience News

Summary: A new study reveals that astrocyte dysfunction may be a driver of cognitive decline and memory loss in people with dementia. This can be caused by a buildup of protein in astrocytes that appears to trigger abnormal antiviral activity resulting in memory loss.

Source: Weill Cornell Medicine

People with dementia have a buildup of proteins in astrocytes that can trigger abnormal antiviral activity and memory loss, according to a preclinical study conducted 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 inThe progress of scienceon 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 their harmful effects on other brain cells and cognition.

Astrocyte dysfunction alone can result in memory loss, even when neurons and other cells are otherwise healthy, said co-senior author Dr. Anna Orr, 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, in mice, that astrocytes can cause cognitive decline through their antiviral activities, which can make neurons hyperactive.

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 supportive roles to 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 involvement in neurocognitive disorders such as dementia is poorly understood.

When researchers, including first author Dr. Avital Licht-Murava, a former postdoctoral associate in the Orr lab, examined tissue samples from deceased individuals who had been diagnosed with Alzheimer’s disease or frontotemporal dementia, they found a accumulation of a protein called TDP-43 in astrocytes within the hippocampus, a brain region crucial for memory.

To understand the effects of this accumulation of proteins, the team conducted a series of experiments on mouse models and laboratory-grown brain cells. Other senior researchers who contributed to the study include Dr. Robert Schwartzat Weill Cornell Medicine and Dr. Robert Froemke at New York University.

In mice, 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 more vulnerable to this pathology. she said.

To understand the causes of memory loss at the molecular level, co-senior author Dr. Adam Orr, research assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute and a member of the Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicines, analyzed the 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 typically found on infiltrating immune cells. To their surprise, the team found that levels of the CXCR3 receptor were elevated in hippocampal neurons and that excessive CXCR3 receptor activity made the neurons hyperactive, said Dr Anna Orr.

Blocking CXCR3 reduced neuronal firing in single neurons, and knocking out CXCR3 in mice by genetic engineering alleviated cognitive deficits caused by accumulation of astrocytic TDP-43, said Dr. Adam Orr. These experiments show that altered astrocytes may play a detrimental role in dementia, he said.

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

For effective therapies, we need to consider astrocytes alongside neurons, said Dr. Anna Orr.

Drugs that target the 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 reused for dementia.

This 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 long-term neurocognitive effects such as memory loss and mental confusion. Abnormal immune activity in astrocytes could contribute to these cognitive effects and increase individuals’ susceptibility to viral infections, which could further degrade 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 brain susceptibility to viral pathogens.

Astrocytes may promote the brain’s resilience or vulnerability to 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.

About this news about neuroscience and memory research

Author: Barbara Prempeh
Source: Weill Cornell University
Contact: Barbara Prempeh – Weill Cornell University
Image: The image is an original 3D by BROKENGRID

Original research: Free access.
“Astrocyte dysregulation of TDP-43 impairs memory by modulating interferon-inducible antiviral pathways and chemokines” by Anna Orr et al. The progress of science

Abstract

Astrocyte dysregulation of TDP-43 impairs memory by modulating interferon-inducible antiviral pathways and chemokines

Transactivating response region DNA-binding protein 43 (TDP-43) pathology is prevalent in dementia, but the cell-type-specific effects of TDP-43 pathology are unclear, and therapeutic strategies to alleviate TDP-related cognitive decline are lacking. TDP-43.

We found that patients with Alzheimer’s disease or frontotemporal dementia have an aberrant accumulation of TDP-43 in hippocampal astrocytes.

In mouse models, the induction of diffuse or hippocampal accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression. These changes were cell-autonomous and correlated with reduced astrocytic defense against infectious viruses.

Among the changes, astrocytes had elevated levels of interferon-inducible chemokines and neurons had elevated levels of the corresponding CXCR3 chemokine receptor in the presynaptic terminals. Stimulation of CXCR3 impaired presynaptic function and promoted neuronal hyperexcitability, similar to the effects of astrocytic dysregulation of TDP-43, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented the TDP-43-related memory leak.

Thus, astrocytic dysfunction of TDP-43 contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions.