venerdì, Giugno 21, 2024

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Brain metabo-PET to anticipate Alzheimer onset: astrocytes and their anomalous cycles under the spotlights

Alzheimer’s disease (AD), one of the major causes of dementia, is known to be associated with neuroinflammation in the brain. While traditional neuroscience has long believed that amyloid beta plaques is been the cause, treatments that target these plaques have had little success in treating or slowing the progression of Alzheimer’s disease. Recently, a team of South Korean scientists 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 revolutionize both the diagnosis and treatment of Alzheimer’s disease. The group demonstrated a mechanism where the astrocytes in the brain uptake elevated levels of acetates, which turns them into hazardous reactive astrocytes. They then went on further to develop a new imaging technique that takes advantage of this mechanism to directly observe the astrocyte-neuron interactions.

On the other hand, Dr. Lee has been a proponent of a novel theory that reactive astrocytes are the real culprit behind Alzheimer’s disease. Reactive astrogliosis, a hallmark of neuroinflammation in AD, often precedes neuronal degeneration or death. The research team previously reported that reactive astrocytes and the monoamine oxidase B (MAO-B) enzyme within these cells can be utilized as therapeutic targets for AD. Recently, they also 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. In this latest research, Lee’s team used PET imaging with radioactive acetate and glucose probes (11C-acetate and 18F-FDG) to visualize the changes in neuronal metabolism in AD patients.

Scientists demonstrated that acetate, the main component of vinegar, is responsible for promoting reactive astrogliosis, which induces putrescine and GABA production and leads to dementia. First, the researchers demonstrated that reactive astrocytes excessively uptake acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. It was discovered that the elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-beta, a well-known toxin protein in AD, is present. The researchers showed 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 the brains with neuroinflammation and AD. Moreover, when they inhibited reactive astrogliosis and astrocytic MCT1 expression in the AD mouse model, they were able to reverse these metabolic alterations.

By using this new imaging strategy, the group discovered that alterations in acetate and glucose metabolism were consistently observed in the AD mouse model and human AD patients. They were able to confirm that a strong correlation exists between the patient’s cognitive function and the PET signals of both 11C-acetate and 18F-FDG. These results suggest that acetate, previously considered an astrocyte-specific energy source, can facilitate reactive astrogliosis and contribute to the suppression of neuronal metabolism. 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. Unfortunately, PET imaging targeting Aβ has had limitations in diagnosing patients, and drugs aimed at removing it as a target for AD treatment have all failed so far. However, this study offers us a new possibility 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 and MCT1 transporter suggests a new target for AD treatment. This means that if PET highliths metabolic disturbances at a certain age, the subject will likely develop cognitive decline. If PET highlights disturbances when the cognitive impairment is already there, it could committ that patient for MCT1 pharmacological modulation.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Nam MH et al. Brain 2023 Apr 17: awad037.

Xie L et al. Alzheim Res Ther. 2023; 15(1):79.

Duan J et al. Front Neurosci. 2023; 17:1137567.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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