Reactive astrocytes as a cause of Alzheimer’s disease?

Korean researchers suggest key role in neuropathogenesis

A team of South Korean scientists:inside has made another breakthrough in Alzheimer’s research. They have discovered a mechanism by which astrocytes take up increased amounts of acetates and convert them into reactive astrocytes. This process was visualized for the first time using a newly developed imaging technique.

Alzheimer’s disease, a major cause of dementia, is associated with neuroinflammation. Amyloid beta plaques were long thought to be responsible, but therapies targeting these plaques have shown little effect. The Korean scientists, however, now postulate reactive astrocytes as the cause. Astrocytes are part of the group of glial cells that function as non-electrically active cells of the nervous system. In the brain, they perform various vital tasks. These cells help organize neuronal networks and isolate neurons from each other through their ramifications. They are considered markers of neuroinflammation in Alzheimer’s disease and often precede neuronal degeneration.

Now, the researchers also confirmed the existence of an activated urea cycle in astrocytes that promotes dementia. However, imaging techniques to observe reactive astrocytes at the clinical level have been lacking. An innovative imaging technique visualizes interactions of reactive astrocytes and neurons, providing new insights into Alzheimer’s pathology and potentially representing a breakthrough for diagnosis and treatment of dementia.

New imaging technique to monitor astrocyte-neuron interactions

Reactive astrogliosis refers to a response of astrocytes in the central nervous system to disturbed homeostasis. It is characterized by changes in the number, shape, and function of astrocytes and plays a key role in neuropathologies such as neurotrauma, stroke, and neurodegenerative diseases. The Korean team demonstrated that astrocytes take up increased amounts of acetates, which converts them into reactive astrocytes. Based on this, the researchers developed an imaging technique to observe astrocyte-neuron interactions.

Alzheimer’s disease, a major cause of dementia, is linked to brain inflammation. Despite the assumption that amyloid beta plaques are the cause, therapies directed at them have shown little or no success in treating or slowing Alzheimer’s.

Reactive astrogliosis often precedes neuronal degeneration or death

The South Korean scientists:led by Director C. Justin LEE of the Center for Cognition and Sociality of the Institute for Basic Science had previously reported reactive astrocytes and the enzyme MAO-B as possible therapeutic targets for AD. Now they also confirmed the existence of a urea cycle in astrocytes that promotes dementia. Despite this significant discovery, there have been no imaging probes for clinical observation of reactive astrocytes.

In this latest research, Lee’s team used positron emission tomography (PET) imaging with radioactive acetate and glucose probes (11 C-acetate and 18 F-FDG) to visualize changes in neuronal metabolism in AD patients.

Dr. NAM Min-Ho, co-author of the study, emphasized the academic and clinical value of this research by visualizing reactive astrocytes, which are considered a major cause of AD. The researchers found that acetate, a major component of vinegar, promotes reactive astrogliosis, which produces putrescine (butane-1,4-diamine) and GABA, leading to dementia.

Inhibition of reactive astrogliosis can reverse metabolic changes

In rodent models, they demonstrated that reactive astrocytes take up excessive acetate, mediated by monocarboxylate transporter-1 (MCT1). They linked this increased acetate uptake to reactive astrogliosis and increased, defective GABA synthesis in astrocytes in the presence of amyloid beta, the known Alzheimer’s toxin protein.

The scientists:demonstrated that PET imaging with 11 C-acetate and 18 F-FDG can be used to visualize reactive astrocyte-induced acetate hypermetabolism and associated neuronal glucose hypometabolism in neuroinflammation and AD. Inhibition of reactive astrogliosis and astrocytic MCT1 expression in AD mouse model could in turn reverse these metabolic changes.

Dr. YUN Mijin, one of the study’s lead authors, notes, “Reactive astrocytes excessively take up acetate compared with normal, which plays an important role in astrocytic inflammatory responses.”

South Korean researchers see new approaches for Alzheimer’s therapy

The new imaging strategy enabled the team to observe consistent metabolic changes in acetate and glucose metabolism in both Alzheimer’s mouse models and human Alzheimer’s patients. The studies confirmed a strong correlation between the patient:s cognitive function and PET signals from both 11 C-acetate and 18 F-FDG. This suggests that acetate, previously considered a specific energy source for astrocytes, may promote reactive astrogliosis and suppress neuronal metabolism.

Dr. RYU Hoon, another author of the study, explains, “We propose a new mechanism that triggers reactive astrogliosis in brain diseases by showing that acetate not only provides energy for astrocytes, but also promotes reactive astrogliosis.”

The study opens new applications of 11 C-acetate and 18 F-FDG PET imaging for early detection of AD. In addition, the newly discovered mechanism of reactive astrogliosis by acetate and MCT1 transporters points to a new target for AD treatment.