Sci Transl Med︱ Xiang Xianyuan and others revealed the crazy sugar phagocytosis of brain immune cells to help early diagnosis of neurodegenerative diseases

Written by Xiang Xianyuan, edited by Wang Sizhen Glucose is the main fuel for brain cells
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The human brain accounts for about 2% of the total body weight, but it consumes 20% of the energy of the body's glucose source
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Energy metabolism can be recorded indirectly through the distribution of glucose in the brain
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Therefore, suppose that where glucose accumulates in the brain, energy requirements and brain activity are particularly high
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In neurodegenerative diseases, such as Alzheimer's disease (Alzheimer's disease, AD) during the occurrence and development of complex changes in brain energy metabolism [1]
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18F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used to detect brain glucose uptake, thereby indirectly measuring the degree of neuronal damage [2]
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However, FDG-PET lacks cell resolution and cannot distinguish the cell types that contribute to the PET signal
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A large number of previous studies have pointed out that synaptic activity is the main source of FDG-PET signals
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Therefore, clinically, the strength of FDG-PET signal is directly linked to neural activity [3-5]
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However, in the early accumulation of AD's pathological molecule β-amyloid (Aβ), the patient's FDG-PET signal showed a short-term regional increase [6-8]
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The reason and mechanism of the regional increase in brain glucose uptake in the pre-neurodegenerative diseases have not been elucidated, which hinders early diagnosis of patients in clinical practice
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On October 13, 2021, Dr.
Xiang Xianyuan (first author of the article), Matthias Brendel, Christian Haass (co-corresponding author) of the University of Munich and others published an online publication on Science Translational Medicine entitled "Microglial activation states drive glucose uptake and The article titled "FDG-PET alterations in neurodegenerative diseases" revises people's understanding of brain FDG-PET imaging and helps early diagnosis of neurodegenerative diseases
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This article states that FDG-PET signal is directly affected by the glucose uptake of immune cells in the brain, and the activity state of immune cells in the brain is the main cause of early changes in FDG-PET signal in patients
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In this article, the author used the colony stimulating factor receptor inhibitor PLX5622 to eliminate the immune cells "microglia" in the brains of wild-type mice and AD model (PS2APP) mice, and then performed long-term longitudinal FDG-PET imaging.
And microglial cell activity-PET (TSPO-PET) imaging study, found that in the control group, AD mice showed unexpected microglial hyperactivity, and glucose uptake has increased dramatically (+17.
6%) (Figure 1) ; In the microglial cell clearance group, the brain glucose uptake and inflammatory response of AD mice fell back to normal levels (Figure 1), which means that the activity of overactive microglia promotes brain glucose uptake
.

More interestingly, in wild-type mice, the glucose uptake in the brain also decreased significantly after the microglia were cleared, which means that under physiological conditions, the glucose uptake by microglia may be higher than expected.
However, it is traditionally believed that the signal of FDG-PET imaging only reflects that neuronal activity may need to be corrected
.

Figure 1 Clearing microglia to reduce brain glucose uptake (picture quoted from: Xiang X et al.
, Sci Transl Med, 2021) Subsequently, in order to determine the effect of microglia on energy metabolism in the brain again, the author used TREM2 (Trigger receptor 2 expressed on myeloid cells, a microglia gene involved in metabolism and activation) Knockout mice were used for long-term longitudinal FDG-PET imaging and TSPO-PET imaging studies
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When AD mice lacked the Trem2 gene, AD mice no longer experienced a sharp increase in glucose uptake at the age of 12 months, but were no different from 12-month-old wild-type mice (Figure 2)
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In wild-type mice, the absence of Trem2 also makes glucose metabolism decrease
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Once again, in mice, a considerable part of the FDG-PET imaging signal comes from the energy metabolism of microglia
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At the same time, in a pathological state (ie, AD mouse model), the abnormal activation of microglia aggravates the sugar phagocytosis of microglia, which leads to an increase in FDG-PET signal
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Figure 2 Loss of Trem2 reduces the activity and sugar phagocytic capacity of microglia, which leads to a decrease in FDG-PET signal (picture quoted from: Xiang X et al.
, Sci Transl Med, 2021) In order to determine neurons and astrocytes The uptake of glucose by cells and microglia and their respective contributions to FDG-PET imaging results.
The authors combined 18F-labeled fluorodeoxyglucose (FDG) and cell sorting technology
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When FDG is injected into the body, fluorodeoxyglucose will be quickly absorbed and stay in the cell, and its radioactive signal can be detected, thereby reflecting the glucose uptake capacity of the cell or tissue
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After injecting this type of glucose into different mouse models, the author sorted out neuron cell bodies, astrocytes and microglia, and detected the radioactive signals released by glucose in various cells to determine the microglia.
The glucose uptake of cells is higher than neuron cell bodies and astrocytes (Figure 3)
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The authors compared various types of cells derived from wild-type mice and Trem2 knockout mice and found that only microglia showed lower glucose uptake (Figure 3)
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When comparing various types of cells derived from AD mice, it was found that only microglia showed increased glucose uptake (Figure 3)
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These two data show that in mice, the changes in FDG-PET signal are due to changes in the glucose uptake of microglia
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This result seriously challenges the current clinical belief that FDG-PET imaging signals only reflect neuronal activity
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Figure 3 The activity of microglia determines its glucose uptake, thereby changing the FDG-PET imaging results (picture quoted from: Xiang X et al.
, Sci Transl Med, 2021) In order to determine the translation and clinical significance of the results, the author A cohort of patients with AD and Tau disease (Table 1) was collected, and FDG-PET imaging and microglial activity-PET (TSPO-PET) imaging were performed
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Twelve AD patients, 21 Tau protein disease patients and control individuals all underwent longitudinal imaging examinations
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The brain area damaged by the patient is a typical disease-related brain area, that is, Aβ-positive AD patients have parieto-occipital nerve degeneration, and Tau protein patients have mild prefrontal degeneration
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In AD patients, the FDG-PET signal of the prefrontal lobe is higher than that of normal individuals, and the FDG-PET signal in this area is significantly positively correlated with TSPO-PET (Figure 4)
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In patients with Tau protein disease, the higher FDG-PET signal in the parietal lobe is also significantly positively correlated with TSPO-PET
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That is to say, in brain areas where there is no obvious nerve damage but pathological changes (ie Aβ-positive or Tau pathological protein), FDG-PET and TSPO-PET signals are significantly positively correlated, and compared with normal individuals, both are Shows a significant increase (Figure 4)
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These results suggest that the activation of microglia in patients directly affects FDG-PET signaling
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This result answers a long-standing clinical question, that is, the overactive energy metabolism of part of the brain area that appears in the early stage of neurodegenerative diseases does not come from overactive neuronal activity, but indicates that the brain area has appeared.
Strong inflammatory response
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Table 1 Patient cohort information (Table quoted from: Xiang X et al.
, Sci Transl Med, 2021) Figure 4 FDG-PET and TSPO-PET imaging results of AD and Tau disease patient cohort (Picture quoted from Xiang X et al .
, Sci Transl Med, 2021) Schematic diagram: The degree of activation of microglia determines its glucose uptake, which affects the patient's glucose-PET signal (Source: Xiang X.
, Brendel M.
, Haass C.
) Conclusion of the article and Discussion, inspiration and prospects.
Energy metabolism can be recorded indirectly through the distribution of glucose in the brain
.

Therefore, where glucose accumulates in the brain, energy requirements and brain activity are particularly high
.

Traditionally, it is believed that only nerve activity, especially nerve synaptic activity, consumes the most energy.
Therefore, clinically, the signal strength of glucose imaging is directly equal to the strength of nerve activity [3-5]
.

Microglia are the most important immune cells in the brain, and the research on their energy consumption in the brain is relatively blank
.

The author’s article fills up this gap and corrects people’s understanding of the signals of glucose imaging, proposing that in addition to neural activity, the activity of microglia can also significantly change the signals of glucose imaging
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 The author used the method of cell separation to explore the amount of glucose uptake by different cell types, and pointed out that the glucose uptake by microglia, especially the activated microglia under disease conditions, is much higher than that of neuron cell bodies and astrocytes.
Plasmic cell
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What needs to be pointed out here is that the disadvantage of this method is the lack of analysis of the energy consumption of nerve synapses
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And this kind of glucose signal can only explain the glucose uptake of cells, and there is no way to further analyze the direction of glucose metabolism
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Therefore, compared with microglia, the absolute energy consumption of synaptic activity is worthy of further investigation
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At the same time, the metabolic direction of microglia ingesting such a high amount of glucose is also worthy of careful investigation.
For example, is it possible for microglia to transmit the decomposed glucose to neurons to help neurons overcome inflammation, or small glue The immune activity of the plasm cell itself needs to consume all the glucose ingested? Despite these shortcomings, combined data from animal models and clinical patients indicate that the immune cells in the brain, microglia, are characterized by large amounts of glucose uptake
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These findings directly changed how we interpret the results of FDG-PET glucose imaging clinically
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It is important for clinicians to understand the source of the image signal
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The understanding that energy metabolism in the brain is almost entirely determined by the function and activity of neurons needs to be revised, because the inflammatory response mediated by microglia has a crucial influence on the uptake of glucose in the brain
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This research is of great significance for the correct interpretation of FDG-PET data and guidance for early diagnosis of neurodegenerative diseases
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At the same time, this study shows that glucose imaging can help as a biomarker to capture the response of microglia to therapeutic interventions in neurodegenerative diseases
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Original link: https:// Xiang Xianyuan (left), the first author, currently working at the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences; Christian Haass (middle), communications Author, University of Munich; Matthias Brendel (right), corresponding author, University of Munich
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