A team of scientists from South Korea, led by Director C. Justin Lee from the Institute for Basic Science's Centre for Cognition and Sociality, has made a significant breakthrough in Alzheimer's disease research. Their findings could potentially revolutionize both the detection and treatment of the disease.
The researchers have discovered a process in which astrocytes, a type of brain cell, absorb large amounts of acetates, leading to the formation of reactive astrocytes that are harmful to the brain. To directly observe the interactions between astrocytes and neurons, they have developed a new imaging technology.
Alzheimer's disease, a major cause of dementia, has been associated with neuroinflammation in the brain. While the traditional understanding of the disease focused on amyloid beta plaques as its origin, treatments targeting these plaques have shown limited effectiveness incuring or slowing down its progression.
Director C. Justin Lee, however, has put forth a new hypothesis that reactive astrocytes are the true cause of Alzheimer's disease. Reactive astrogliosis, a sign of neuroinflammation in Alzheimer's, often precedes the degeneration or death of neurons.
Lee's team previously identified reactive astrocytes and the enzyme monoamine oxidase B (MAO-B) present in these cells as potential targets for Alzheimer's disease treatment. They have recently discovered the presence of a urea cycle in astrocytes and demonstrated that an activated urea cycle contributes to dementia. However, there is currently a lack of brain imaging tools capable of observing and diagnosing reactive astrocytes.
The team utilized positron emission tomography (PET) imaging with radioactive acetate and glucose probes ( 11 C-acetate and 18 F-FDG) to visualize changes in brain metabolism in Alzheimer's patients. They also found that acetate, a major component of vinegar, promotes reactive astrogliosis, leading to putrescine and GABA synthesis, which contribute to dementia. In animal models of both reactive astrogliosis and Alzheimer's disease, the researchers observed that reactive astrocytes absorb excessive amounts of acetate through increased monocarboxylate transporter-1 (MCT1) when an amyloid beta is present. This increased acetate absorption is associated with reactive astrogliosis and abnormal production of astrocytic GABA.
Using PET imaging with 11 C-acetate and 18 F-FDG, the researchers were able to visualize the acetate hypermetabolism induced by reactive astrocytes and the concomitant glucose hypometabolism in the brains of individuals with neuroinflammation and Alzheimer's disease. They were also able to reverse these metabolic changes in an Alzheimer's disease mouse model by inhibiting reactive astrogliosis and the expression of astrocytic MCT1.
Through this novel imaging technique, the researchers consistently observed changes in acetate and glucose metabolism in both the Alzheimer's disease mouse model and human patients. They confirmed a strong correlation between cognitive function and the PET findings of 11 C- acetate and 18 F-FDG, suggesting that acetate, previously considered an energy source specific to astrocytes, can accelerate reactive astrogliosis and contribute to the suppression of neuronal metabolism.
Until now, amyloid beta (Aβ) has been the primary suspect as the cause of Alzheimer's disease and the main focus of dementia research. However, PET imaging targeting Aβ has limitations in diagnosing patients, and drugs aimed at removing Aβ as a treatment target for Alzheimer's disease have been unsuccessful.
This study introduces the potential use of 11 C-acetate and 18 F-FDG PET imaging for the early detection of Alzheimer's disease. Moreover, the newly discovered mechanism of reactive astrogliosis through acetate and the MCT1 transporter proposes a novel target for Alzheimer's disease treatment.
