“Revolutionary Brain Imaging Technology for Early Diagnosis of Alzheimer’s Disease through Reactive Astrocytes and Decreased Neuronal Metabolism”

2023-04-23 14:51:00

The path to imaging reactive astrocytes in the brain for early diagnosis of Alzheimer’s disease has been opened. The research team led by Director Lee Chang-joon of the Center for Cognition and Sociality at the Institute for Basic Science (IBS), together with Professor Yoon Mi-jin of the Department of Nuclear Medicine at Severance Hospital (Director Ha Jong-won), and the research team of Senior Researcher Ryu Hoon at the Korea Institute of Science and Technology (KIST) Brain Science Research Center Reactive astrocytes in the brain of Alzheimer’s diseaseand due to Decreased neuronal metabolismcast success in imagingAnd the mechanism was revealed.

Alzheimer’s disease, one of the leading causes of senile dementia, is well known to accompany brain inflammatory responses. When a brain inflammatory response occurs, one of the first symptoms to appear is reactive astrogliosis, in which the size and function of astrocytes, which are the largest number of star-shaped non-neuronal cells in the brain, change.

The Center for Cognition and Sociality reported in a previous study that reactive astrocytes expressed the enzyme MAO-B to produce the inhibitory neurotransmitter GABA from putrescine, causing memory decline. . Recently, we confirmed the existence of the urea circuit that generates elements within astrocytes, and identified that the activated urea circuit promotes dementia. However, despite this clinical importance of reactive astrocytes, a cranial nerve imaging technique that can meaningfully image, observe and diagnose these cells at the clinical level has not yet been developed.

The researchers found that carbon 11-acetic acid (¹¹C-acetate) and fluorine 18-fluorodeoxyglucose (¹⁸F-FDG) together with positron emission tomography (PET) imaging, showing that reactive astrocytes in Alzheimer’s patients and the resulting decrease in glucose metabolism in neurons can be imaged. PET is a technology that measures positrons emitted by radiopharmaceuticals that selectively bind to specific substances to show physiological, chemical, and functional three-dimensional images of the human body. ¹¹C-Acetate is mainly used for cancer diagnosis by imaging cells that absorb acetic acid, a tracer. ¹⁸F-FDG was used to track glucose and motor activity in the brain, respectively.

As a result of confirming the reactive astrocyte-derived animal model through PET imaging, the research team found that reactive astrocyte activation activates acetic acid metabolism in reactive astrocytes and induces inhibition of glucose metabolism in peripheral neurons. In addition, multilateral analyzes including immunohistochemical and electrophysiological methods along with PET images revealed that acetic acid promotes reactive astrocytes, leading to the production of putrescine and GABA, leading to dementia.

Acetic acid, commonly known as ‘vinegar’, functions as an energy source for astrocytes. Acetic acid is excessively absorbed in reactive astrocytes by Monocarboxylate transporter 1 (MCT1), which is specifically expressed in astrocytes, Reactive astrocytes were further promoted. In addition, acetic acid promoted reactive astrocytes induced in astrocytes treated with a toxic substance, amyloid beta, activated urea cycle, and consequently putrescine and GABA production.

Conversely, when reactive astrocytes were suppressed or the expression of MCT1 was suppressed, astrocyte metabolism and glucose metabolism in peripheral neurons were restored to normal. These metabolic changes were found in various Alzheimer’s animal models and in real Alzheimer’s patients, and the more severe the metabolic changes, the greater the cognitive function of Alzheimer’s patients.

Increased 11C-acetic acid uptake and decreased 18F-FDG uptake observed through PET imaging in animal models of reactive astrocytes When reactive astrocytes were induced in the area marked in yellow, 11C-acetic acid uptake increased (orange) and 18F-FDG uptake increased (orange). It was confirmed that FDG uptake decreased (blue). These changes were restored to normal levels when reactive astrocytes were inhibited with the MAO-B inhibitor (KDS2010) (left) or when the expression of the MCT1 gene was inhibited (right). Source: IBS

So far, amyloid beta has been known to be the main cause of dementia. However, PET imaging that targets this has limitations in diagnosing patients in clinical practice. In addition, all dementia treatments that aim to eliminate amyloid beta have failed so far.

This study ¹¹with C-Acetate ¹⁸It has been shown that PET imaging using F-FDG can be used to diagnose reactive astrocytes and functionally inhibited neurons at a clinical level, showing the possibility of early diagnosis of Alzheimer’s disease. Above all, by revealing the mechanism of promoting reactive astrocytes by acetic acid and the MCT1 transporter, a new target for dementia treatment was presented.

Minho Nam, senior researcher at KIST, said, “This study has great academic and clinical value as it shows that reactive astrocytes, which have recently been highlighted as a key cause of dementia, can be directly visualized in the patient’s brain.” KIST Principal Researcher Hoon Ryu said, “We found that acetic acid not only acts as an energy source for astrocytes, but also promotes reactive astrocytes, suggesting a new mechanism by which reactive astrocytes are induced in brain diseases.”

The results of the study were published online on April 17 in Brain, an academic journal in the field of brain science.

논문명 : Visualizing reactive astrocyte-neuron interaction in Alzheimer’s disease using ¹¹C-acetate and ¹⁸F-FDG

# Glossary

1. Reactive astrogliosis

Astrocytes usually play a role in maintaining brain homeostasis, but it is known that the number and size of astrocytes increase and are accompanied by various functional changes in brain diseases including dementia. The state of astrocytes changed in this way is called a ‘reactive astrocyte’.

2. Monoamine Oxidase B (MAO-B)

It is a protein present in mitochondria in cells and is an enzyme that promotes the degradation of monoamines, and is known to play an important role in the metabolism of neurotransmitters in the nervous system. It is known to be expressed mainly in astrocytes among brain cells, and its activity is increased in reactive astrocytes.

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