Figure 1. Augmentation of acetate uptake, moderated by MCT1, facilitates Aβ-induced GABA release in reactive astrocyte. A. Blockade impact of MCT1 inhibitor on 14C-acetate uptake in primary cultured astrocytes. B. Blockade effect of Mct1 gene-silencing on 14C-acetate uptake in primary cultured astrocytes. C. Representative images showing GFAP and MCT1 expressions in main cultured astrocytes 48 hours after adenovirus treatment. D. The adenovirus effect on 14C-acetate uptake. E. Schematic diagram of in vivo micro-PET imaging of adenovirus design. F. Representative images showing GFAP and MCT1 expressions in adenovirus model. G. Schematic diagram of sniffer spot to tape-record GABA present. H. Representative traces of Ca2+ signal (top) and GABA existing (bottom). Credit: Institute for Basic Science
On the other hand, Director C. Justin LEE has been a supporter of a novel theory that reactive astrocytes are the genuine culprit behind Alzheimers illness. Reactive astrogliosis, a trademark of neuroinflammation in advertisement, often precedes neuronal degeneration or death.
Lees research study group previously reported that reactive astrocytes and the monoamine oxidase B (MAO-B) enzyme within these cells can be used as therapeutic targets for AD. Recently, they likewise validated the existence of a urea cycle in astrocytes and demonstrated that the triggered urea cycle promotes dementia. In spite of the medical value of reactive astrocytes, brain neuroimaging probes that can observe and identify these cells at a scientific level have actually not yet been developed.
In this most current research study, Lees group utilized positron emission tomography (PET) imaging with radioactive acetate and glucose probes (11C-acetate and 18F-FDG) to visualize the changes in neuronal metabolism in AD clients.
Dr. NAM Min-Ho, one of the very first authors of this paper, specified, “This study shows considerable scholastic and clinical value by straight picturing reactive astrocytes, which have actually recently been highlighted as a primary reason for advertisement.”
11C-acetate and 18F-FDG in vivo micro-PET imaging in adenovirus design (reactive astrogliosis design). A. Left, parametric images from a voxel-based comparison of 11C-acetate and 18F-FDG PET imaging in adenovirus model with or without KDS2010 treatment.
Furthermore, they showed that acetate, the main component of vinegar, is accountable for promoting reactive astrogliosis, which causes putrescine and GABA production and leads to dementia. First, the scientists demonstrated that reactive astrocytes exceedingly uptake acetate through raised monocarboxylate transporter-1 (MCT1) in rodent designs of both reactive astrogliosis and AD (Figure 1A to 1F). It was found that the elevated acetate uptake is associated with reactive astrogliosis and improves the aberrant astrocytic GABA synthesis when amyloid-beta, a popular toxic substance protein in advertisement, is present (Figure 1G & & 1H).
The researchers showed that PET imaging with 11C-acetate and 18F-FDG can be utilized to picture the reactive astrocyte-induced acetate hypermetabolism and associated neuronal glucose hypometabolism in the brains with neuroinflammation and AD (Figure 2A). Additionally, when the researchers prevented reactive astrogliosis and astrocytic MCT1 expression in the advertisement mouse design, they were able to reverse these metabolic changes.
11C-acetate and 18F-FDG imaging for visualizing reactive astrogliosis and the associated neuronal glucose hypometabolism in Advertisement clients brains. A. Representative PET images of 11C-acetate and 18F-FDG in control and AD clients.
Dr. YUN Mijin commented, “Reactive astrocytes revealed metabolic problems that excessively uptake acetate compared to typical state. We discovered that the acetate plays an essential function in promoting astrocytic inflammatory reactions.”
By utilizing this brand-new imaging method, the group found that modifications in acetate and glucose metabolic process were regularly observed in the AD mouse model and human AD clients (Figure 3A). They were able to verify that a strong connection exists between the clients cognitive function and the PET signals of both 11C-acetate and 18F-FDG (Figure 3B). These results recommend that acetate, formerly considered an astrocyte-specific energy source, can assist in reactive astrogliosis and contribute to the suppression of neuronal metabolic process.
Dr. RYU Hoon remarked, “By demonstrating that acetate not just serves as an energy source for astrocytes but also helps with reactive astrogliosis, we suggested a new system that causes reactive astrogliosis in brain diseases.”
Animal imaging targeting Aβ has had constraints in detecting patients, and drugs intended at removing it as a target for AD treatment have all stopped working so far. In addition, the newly found mechanism of reactive astrogliosis through acetate and MCT1 transporter recommends a brand-new target for Advertisement treatment.
Dr. C. Justin LEE stated, “We confirmed a substantial recovery when inhibiting MCT1, astrocyte-specific acetate transportation, in an AD animal design,” and included, “We anticipate MCT1 can be a new healing target for advertisement.”
Reference: “Visualizing reactive astrocyte-neuron interaction in Alzheimers illness utilizing 11C-acetate and 18F-FDG” by Min-Ho Nam, Hae Young Ko, Dongwoo Kim, Sangwon Lee, Yongmin Mason Park, Seung Jae Hyeon, Woojin Won, Jee-In Chung, Seon Yoo Kim, Han Hee Jo, Kyeong Taek Oh, Young-Eun Han, Gwan-Ho Lee, Yeon Ha Ju, Hyowon Lee, Hyunjin Kim, Jaejun Heo, Mridula Bhalla, Ki Jung Kim, Jea Kwon, Thor D. Stein, Mingyu Kong, Hyunbeom Lee, Seung Eun Lee, Soo-Jin Oh, Joong-Hyun Chun, Mi-Ae Park, Ki Duk Park, Hoon Ryu, Mijin Yun, C. Justin Lee., 16 April 2023, Brain.DOI: 10.1093/ brain/awad037.
South Korean scientists have found that reactive astrocytes, rather than amyloid-beta plaques, might be the primary cause of Alzheimers illness. The scientists found that acetate, formerly believed to be an energy source for astrocytes, can promote reactive astrogliosis and suppress neuronal metabolism.
Animal imaging of reactive astrocyte-neuron interaction exposes new insights into Alzheimers illness pathology, providing a possible advancement in diagnosis and treatment.
Just recently, a group of South Korean researchers led by Director C. Justin LEE of the Center for Cognition and Sociality within the Institute for Basic Science made a new discovery that can change both the medical diagnosis and treatment of Alzheimers Disease. The group showed a mechanism where the astrocytes in the brain uptake elevated levels of acetates, which turns them into harmful reactive astrocytes. They then went on additional to develop a brand-new imaging method that takes benefit of this mechanism to straight observe the astrocyte-neuron interactions.
Alzheimers illness (ADVERTISEMENT), among the significant reasons for dementia, is known to be associated with neuroinflammation in the brain. While standard neuroscience has long thought that amyloid beta plaques is been the cause, treatments that target these plaques have actually had little success in slowing the progression or dealing with of Alzheimers disease.
The scientists found that acetate, formerly thought to be an energy source for astrocytes, can promote reactive astrogliosis and suppress neuronal metabolic process. The group showed a mechanism where the astrocytes in the brain uptake elevated levels of acetates, which turns them into harmful reactive astrocytes. Enhancement of acetate uptake, moderated by MCT1, helps with Aβ-induced GABA release in reactive astrocyte. The researchers demonstrated that reactive astrocytes exceedingly uptake acetate through raised monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD (Figure 1A to 1F). In addition, the recently found system of reactive astrogliosis through acetate and MCT1 transporter suggests a new target for Advertisement treatment.
