Researchers headed by a team at the Institute for Basic Science’s Center for Cognition and Sociality in South Korea reported on a discovery that they claim could revolutionize the diagnosis and treatment of Alzheimer’s disease (AD).

Headed by director C. Justin Lee, PhD, the team discovered a mechanism whereby astrocytes in the brain take up increased amounts of acetate, turning them into hazardous “reactive astrocytes.” The scientists developed a new imaging technique that takes advantage of this mechanism to directly observe astrocyte-neuron interactions. Reporting on their studies in Brain, they say their findings suggest that “acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.” Lee et al.’s paper is titled, “Visualizing reactive astrocyte-neuron interaction in Alzheimer’s disease using 11C-acetate and 18F-FDG.” In their paper, the researchers concluded, “… our findings provide the first in vivo evidence for the critical role of reactive astrogliosis in human AD symptomatology, which has been suspected for several decades based on animal studies.”

AD, one of the major causes of dementia, is known to be associated with neuroinflammation in the brain. Traditional neuroscience has long considered a causative role for amyloid beta (Aβ) plaques, but treatments that target these plaques have had little success in treating or slowing the progression of AD.

Astrocyte cells in the brain support neighboring neurons both physically and chemically, under physiological conditions, the authors explained. But in response to various physical and chemical insults astrocytes dynamically change their properties, including their morphology and function. “The responding astrocytes are termed reactive astrocytes,” the team continued. Yet while reactive astrogliosis is a hallmark of neuroinflammation in AD and often precedes neuronal degeneration or death.

Lee is a proponent of a novel theory that it is these reactive astrocytes that represent the real culprit behind Alzheimer’s disease. Lee’s research team had previously reported that reactive astrocytes and the monoamine oxidase B (MAO-B) enzyme in the reactive astrocytes can be utilized as therapeutic targets for AD. Other studies have reported that reactive astrocytes aberrantly produce GABA to inhibit neighboring neuronal activity and glucose metabolism, “which critically contributes to neuronal dysfunction in AD.” So, they noted, “… in vivo imaging of reactive astrogliosis should have a considerable diagnostic value at the early stages of AD … Based on recent reports demonstrating the abundant expression of monoamine oxidase B (MAO-B) in the reactive astrocytes of AD, PET of MAO-B has received some endorsement for the in vivo imaging of reactive astrogliosis.”

Lee’s team also recently confirmed the existence of a urea cycle in astrocytes and demonstrated that the activated urea cycle promotes dementia. However, despite the clinical importance of reactive astrocytes, brain neuroimaging probes that can observe and diagnose these cells at a clinical level have not yet been developed. “Several previous studies even demonstrated that reactive astrogliosis can directly cause extensive neuronal death” the team pointed out, but a clinically validated neuroimaging probe to visualize the reactive astrogliosis has not yet been developed.

In this latest research, Lee’s team used 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 patients. Co-first author, Min-Ho Nam, PhD, at the Korea Institute of Science and Technology (KIST) said, “This study demonstrates significant academic and clinical value by directly visualizing reactive astrocytes, which have recently been highlighted as a main cause of AD.”

Their studies demonstrated that acetate, the main component of vinegar, is responsible for promoting reactive astrogliosis, which induces putrescine and GABA production and leads to dementia. The researchers first demonstrated that reactive astrocytes excessively uptake acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. “We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD,” the investigators stated. The studies also showed that this elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when the AD-related protein, Aβ, is present.

Through their new work, the team confirmed that PET imaging with 11C-acetate and 18F-FDG can be used to visualize the reactive astrocyte-induced acetate hypermetabolism and associated neuronal glucose hypometabolism in brains with neuroinflammation and AD. And when researchers inhibited reactive astrogliosis and astrocytic MCT1 expression in the AD mouse model, they were able to reverse these metabolic alterations. Their results, they wrote, “… together indicate the necessity of astrocytic MCT1 for aberrant astrocytic GABA synthesis, exacerbated tonic inhibition of hippocampal neurons, and impaired spatial memory in AD model mice.”

Using this new imaging strategy the group discovered that changes in acetate and glucose metabolism were consistently observed in the AD mouse model and in human AD patients. “Our study demonstrates that reactive astrocytes aberrantly absorb acetate in the affected brain regions of both AD patients and animal models, which in turn boosts GABA synthesis,” they wrote.

The team was able to confirm that a strong correlation exists between patient cognitive function and the PET signals of both 11C-acetate and 18F-FDG. “Taken together, these results indicate the reactive astrogliosis visualized by 11C-acetate and the associated neuronal dysfunction visualized by 18F-FDG to be highly correlated with cognitive impairment for AD patients,” the scientists stated.

These combined results suggest that acetate, previously considered an astrocyte-specific energy source, can facilitate reactive astrogliosis and contribute to the suppression of neuronal metabolism. Co-author Mijin Yun PhD, at Severance Hospital, Yonsei University College of Medicine commented, “Reactive astrocytes showed metabolic abnormalities that excessively uptake acetate compared to normal state. We found that the acetate plays an important role in promoting astrocytic inflammatory responses.” KIST co-author Hoon Ryu, PhD, further remarked, “By demonstrating that acetate not only acts as an energy source for astrocytes but also facilitates reactive astrogliosis, we suggested a new mechanism that induces reactive astrogliosis in brain diseases.”

Until now, amyloid beta (Aβ) has been suspected as the main cause of AD, and thus they have been the main focus of most dementia research. However, PET imaging focused on Aβ had limitations for diagnosing patients, and drugs targeting Aβ for AD therapy have all failed so far. The newly reported study by Lee et al., points to the potential use of using 11C-acetate and 18F-FDG PET imaging for early diagnosis of AD. In addition, the newly discovered mechanism of reactive astrogliosis through acetate uptake by MCT1 transporter suggests a new target for AD treatment. Lee noted, “We confirmed a significant recovery when inhibiting MCT1, astrocyte-specific acetate transport, in an AD animal model … we expect MCT1 can be a new therapeutic target for AD.”

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