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Written by Cheng Jinbo, edited by Cheng Jinbo, Wang Sizhen Alzheimer's disease (Alzheimer's disease, AD) is one of the most common neurodegenerative diseases.
The disease rate keeps increasing with age
.
The excessive deposition of β-amyloid (β-Amyloid, Aβ) and the hyperphosphorylation of Tau protein are important pathological features of AD, and it is also considered to be an important cause of nerve damage
.
These processes are closely related to calcium homeostasis, which gradually formed the calcium homeostasis hypothesis of AD [1, 2]
.
However, the role of calcium homeostasis in microglia activation and neuroinflammation is currently unclear
.
On August 25, 2021, the joint team of Professor Yuan Zengqiang from the Academy of Military Medical Sciences and Associate Professor Cheng Jinbo from Minzu University of China published a research paper entitled "Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer's disease pathology" online in Science Advances, revealing The important role of Calhm2 in the activation of microglia, and provides a potential therapeutic target for targeting microglia-mediated neuroinflammation-related diseases including AD
.
Associate Professor Cheng Jinbo from Minzu University of China and Dr.
Dong Yuan from Qingdao University are the co-first authors of the paper
.
In recent years, the role of calcium homeostasis regulatory proteins in AD has received more and more attention
.
This family includes 3 members, namely Calhm1, Calhm2 and Calhm3.
Among them, Calhm1 can regulate neuronal calcium homeostasis, Aβ production, nerve cell susceptibility, etc.
Its mutant P86L is closely related to the occurrence of AD [2]
.
The team’s previous study found that Calhm1 protein is not expressed in the mouse brain, and knockout mice did not show significant cognitive impairment [2].
Follow-up studies have shown that Calhm1 is mainly expressed in type II taste bud cells and regulates ATP release and taste [2] 3]
.
Calhm2 is widely expressed in the mouse brain, and Calhm2 gene knockout can inhibit the release of ATP from astrocytes and cause depression-like phenotypes in mice [4]
.
At present, the protein structure of Calhm2 has been resolved [5, 6], but the role of Calhm2 in AD is not clear
.
In this study, first, the researchers found that Calhm2 in the calcium homeostasis regulatory protein family increased significantly in clinical AD patients and AD animal model mice (Figure 1), suggesting that Calhm2 may be involved in the occurrence and development of AD
.
Figure 1.
Calhm2 increased significantly in AD patients and animal models (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) Therefore, researchers further used Calhm2 gene knockout mice whole body and combined with AD animal models (5×FAD), it was found that Calhm2 systemic knockout significantly improved the cognitive impairment of mice, and significantly reduced Aβ deposition, glial cell activation, and neuroinflammation
.
However, Calhm2 knockout did not affect the production of Aβ.
At the same time, researchers used neuronal conditional Calhm2 knockout mice (Calhm2flox/flox; CamKIIα-iCre) combined with 5×FAD model mice and found neuronal conditional Calhm2 knockout The addition does not affect the formation and deposition of Aβ (Figure 2)
.
Figure 2.
Calhm2 knockout significantly improved spatial cognitive impairment in AD model mice (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) Next, the researchers used microglia to condition Calhm2 gene knockout In addition to mice (Calhm2flox/flox:Cx3cr1-CreER), combined with AD animal models (5×FAD), it was found that the loss of Calhm2 in microglia significantly reduced Aβ deposition and neuroinflammation in the mouse brain, and significantly improved AD model mice The cognitive impairment suggests that Calhm2 plays an important role in the activation of microglia
.
The combined results also indicate the cell type specificity of Calhm2 expression and function (Figure 3)
.
Figure 3.
Microglia-specific Calhm2 knockout significantly improved the spatial cognitive impairment of AD model mice (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) In order to further clarify the Calhm2 gene in microglia For the mechanism of cell activation, researchers used single-cell dissociation of mouse brain tissue, sorted microglia, and performed micro-genome sequencing
.
The results of biosynthesis analysis showed that Calhm2 knockout of microglia significantly reduced the NF-κB signaling pathway, ROS pathway, IL-6/JAK/STAT3 pathway, inflammatory factor levels, etc.
, suggesting that Calhm2 knockdown significantly inhibited microglia Inflammation activation capacity (Figure 4)
.
Figure 4.
Microglial cell specific Calhm2 knockout significantly reduces its inflammation activation ability (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) In order to further clarify the role of Calhm2 in microglial inflammation activation Researchers used Calhm2 systemic knockout mice and microglial conditional Calhm2 knockout mice (Calhm2flox/flox:Cx3cr1-CreER) to construct an acute inflammation model of intraperitoneal injection of bacterial lipopolysaccharide LPS
.
The results showed that both systemic knockout of Calhm2 gene and conditional knockout of microglia can significantly inhibit the level of neuroinflammation in the brain and the activation of microglia (Figure 5)
.
Figure 5.
Calhm2 knockout significantly inhibits LPS-induced neuroinflammation and microglia activation (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) In terms of looking for the mechanism by which Calhm2 acts on microglia activation Using the calcium signal detection method, the researchers found that Calhm2 knockout significantly inhibited the calcium influx in microglia; through immunoprecipitation technology, it was found that Calhm2 can interact with P2X7, a gland that is highly expressed in microglia.
Glycoside receptors play an important role in AD; at the same time, Calhm2 knockout significantly reduces the protein level of cell membrane P2X7, significantly inhibits the membrane current of P2X7 and the activation of downstream NLRP3 inflammasomes, suggesting that Calhm2 can regulate the calcium homeostasis of microglia , And P2X7-mediated activation of NLRP3 inflammasome (Figure 6)
.
Figure 6.
Calhm2 knockout significantly inhibits calcium influx and P2X7 membrane current (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) Figure 7.
Calhm2 regulation of microglia activation and participation in AD model diagram (Picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) Conclusion and discussion of the article, inspiration and outlook This study uses AD patient samples and AD animal models, combined with Calhm2 whole body knockout mice and conditional knockout Mice have clarified the important role of Calhm2 in the activation of microglia, providing an important target for targeting microglia activation and neuroinflammation (Figure 7)
.
In addition, Calhm2 mediates calcium influx in microglia, and Calhm2 can interact with P2X7.
Calhm2 knockout significantly inhibits the function of P2X7, suggesting that Calhm2-mediated calcium homeostasis plays a key role in microglia activation
.
However, the mechanism of the up-regulation of Calhm2 in AD patients and AD model animals is still unclear.
In addition, the mechanism of Calhm2's regulation of P2X7 is also in urgent need of in-depth study
.
In conclusion, this study further enriches and expands the calcium homeostasis theory in the AD field, reveals the molecular mechanism of neuroinflammation, and provides potential intervention strategies for targeted neuroinflammation treatment of AD (Figure 7)
.
Original link: https://advances.
sciencemag.
org/content/7/35/eabe3600 The corresponding author of the paper is Associate Professor Cheng Jinbo of the Minzu University of China, and Researcher Yuan Zengqiang of the Academy of Military Medicine
.
The first author is Associate Professor Cheng Jinbo from Minzu University of China, and Dr.
Dong Yuan from Qingdao University.
This work was greatly assisted by Professor Yu Ye from Shanghai Jiaotong University and Dr.
Wang Liang from the Institute of Microbiology, Chinese Academy of Sciences
.
This work was jointly funded by key projects of the National Natural Science Foundation of China and general projects
.
Selected articles from previous issues [1] New Discovery of EMBO J︱! AGHGAP11B promotes the expansion of the neocortex into adulthood and improves cognitive ability [2] Cell Death Differ︱ Qi Yitao/Wu Hongmei and others cooperate to reveal the molecular mechanism of SUMO modification regulating neurogenesis in adult mice [3] Cereb Cortex︱A2A receptor antagonist can Reversing the sequence learning impairment induced by abnormal aggregation of α-Syn [4] Neuron︱Nicotine promotes the new discovery of anxiety-the important role of inhibiting the ventral tegmental area-amygdala dopamine pathway [5] Int J Mol Sci︱ Frontier review Interpretation: Pathophysiological response and role of astrocytes in traumatic brain injury [6] Cereb Cortex | Wang Lang's research group revealed that astrocytes have experience-dependent steady-state plasticity [7] New discovery in Nature︱! The social spread of maternal behavior caused by oxytocin neurons [8] Genome Biol︱ Ding Junjun’s team systematically draws a three-dimensional structure map of chromatin during phase separation, dissolution and reconstruction [9] New Brain︱ method! Plasma astrocyte proliferation GFAP or a new potential marker for Alzheimer’s disease detection [10] Autophagy︱Zhang Zhidong’s team reveals a new mechanism for STING1 to induce autophagy to regulate RNA virus infection [11] Nature︱ Astrocytes Source IL-3 regulates the function of microglia, relieves AD pathological changes and cognitive impairment [12] JCI︱ Gao Tianming’s research group reveals that the prefrontal cortex has an opposite role in regulating anxiety and fear in the neural circuit [13] eLife︱ Single cell sequencing and neural circuit analysis jointly reveal the molecular genetic coding mechanism of brain initiation of attack/defense instincts [14] Nature︱Frontier! GluDs transduce different pre-synaptic signals to different post-synaptic receptor responses.
References (Swipe up and down to view) [1] Khachaturian, ZS, Calcium, membranes, aging, and Alzheimer's disease.
Introduction and overview.
Ann NY Acad Sci, 1989.
568: p.
1-4.
[2] Alzheimer's Association Calcium Hypothesis, W .
,
The disease rate keeps increasing with age
.
The excessive deposition of β-amyloid (β-Amyloid, Aβ) and the hyperphosphorylation of Tau protein are important pathological features of AD, and it is also considered to be an important cause of nerve damage
.
These processes are closely related to calcium homeostasis, which gradually formed the calcium homeostasis hypothesis of AD [1, 2]
.
However, the role of calcium homeostasis in microglia activation and neuroinflammation is currently unclear
.
On August 25, 2021, the joint team of Professor Yuan Zengqiang from the Academy of Military Medical Sciences and Associate Professor Cheng Jinbo from Minzu University of China published a research paper entitled "Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer's disease pathology" online in Science Advances, revealing The important role of Calhm2 in the activation of microglia, and provides a potential therapeutic target for targeting microglia-mediated neuroinflammation-related diseases including AD
.
Associate Professor Cheng Jinbo from Minzu University of China and Dr.
Dong Yuan from Qingdao University are the co-first authors of the paper
.
In recent years, the role of calcium homeostasis regulatory proteins in AD has received more and more attention
.
This family includes 3 members, namely Calhm1, Calhm2 and Calhm3.
Among them, Calhm1 can regulate neuronal calcium homeostasis, Aβ production, nerve cell susceptibility, etc.
Its mutant P86L is closely related to the occurrence of AD [2]
.
The team’s previous study found that Calhm1 protein is not expressed in the mouse brain, and knockout mice did not show significant cognitive impairment [2].
Follow-up studies have shown that Calhm1 is mainly expressed in type II taste bud cells and regulates ATP release and taste [2] 3]
.
Calhm2 is widely expressed in the mouse brain, and Calhm2 gene knockout can inhibit the release of ATP from astrocytes and cause depression-like phenotypes in mice [4]
.
At present, the protein structure of Calhm2 has been resolved [5, 6], but the role of Calhm2 in AD is not clear
.
In this study, first, the researchers found that Calhm2 in the calcium homeostasis regulatory protein family increased significantly in clinical AD patients and AD animal model mice (Figure 1), suggesting that Calhm2 may be involved in the occurrence and development of AD
.
Figure 1.
Calhm2 increased significantly in AD patients and animal models (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) Therefore, researchers further used Calhm2 gene knockout mice whole body and combined with AD animal models (5×FAD), it was found that Calhm2 systemic knockout significantly improved the cognitive impairment of mice, and significantly reduced Aβ deposition, glial cell activation, and neuroinflammation
.
However, Calhm2 knockout did not affect the production of Aβ.
At the same time, researchers used neuronal conditional Calhm2 knockout mice (Calhm2flox/flox; CamKIIα-iCre) combined with 5×FAD model mice and found neuronal conditional Calhm2 knockout The addition does not affect the formation and deposition of Aβ (Figure 2)
.
Figure 2.
Calhm2 knockout significantly improved spatial cognitive impairment in AD model mice (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) Next, the researchers used microglia to condition Calhm2 gene knockout In addition to mice (Calhm2flox/flox:Cx3cr1-CreER), combined with AD animal models (5×FAD), it was found that the loss of Calhm2 in microglia significantly reduced Aβ deposition and neuroinflammation in the mouse brain, and significantly improved AD model mice The cognitive impairment suggests that Calhm2 plays an important role in the activation of microglia
.
The combined results also indicate the cell type specificity of Calhm2 expression and function (Figure 3)
.
Figure 3.
Microglia-specific Calhm2 knockout significantly improved the spatial cognitive impairment of AD model mice (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) In order to further clarify the Calhm2 gene in microglia For the mechanism of cell activation, researchers used single-cell dissociation of mouse brain tissue, sorted microglia, and performed micro-genome sequencing
.
The results of biosynthesis analysis showed that Calhm2 knockout of microglia significantly reduced the NF-κB signaling pathway, ROS pathway, IL-6/JAK/STAT3 pathway, inflammatory factor levels, etc.
, suggesting that Calhm2 knockdown significantly inhibited microglia Inflammation activation capacity (Figure 4)
.
Figure 4.
Microglial cell specific Calhm2 knockout significantly reduces its inflammation activation ability (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) In order to further clarify the role of Calhm2 in microglial inflammation activation Researchers used Calhm2 systemic knockout mice and microglial conditional Calhm2 knockout mice (Calhm2flox/flox:Cx3cr1-CreER) to construct an acute inflammation model of intraperitoneal injection of bacterial lipopolysaccharide LPS
.
The results showed that both systemic knockout of Calhm2 gene and conditional knockout of microglia can significantly inhibit the level of neuroinflammation in the brain and the activation of microglia (Figure 5)
.
Figure 5.
Calhm2 knockout significantly inhibits LPS-induced neuroinflammation and microglia activation (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) In terms of looking for the mechanism by which Calhm2 acts on microglia activation Using the calcium signal detection method, the researchers found that Calhm2 knockout significantly inhibited the calcium influx in microglia; through immunoprecipitation technology, it was found that Calhm2 can interact with P2X7, a gland that is highly expressed in microglia.
Glycoside receptors play an important role in AD; at the same time, Calhm2 knockout significantly reduces the protein level of cell membrane P2X7, significantly inhibits the membrane current of P2X7 and the activation of downstream NLRP3 inflammasomes, suggesting that Calhm2 can regulate the calcium homeostasis of microglia , And P2X7-mediated activation of NLRP3 inflammasome (Figure 6)
.
Figure 6.
Calhm2 knockout significantly inhibits calcium influx and P2X7 membrane current (picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) Figure 7.
Calhm2 regulation of microglia activation and participation in AD model diagram (Picture quoted from: Cheng et al.
, Sci Adv 2021; 7: eabe3600) Conclusion and discussion of the article, inspiration and outlook This study uses AD patient samples and AD animal models, combined with Calhm2 whole body knockout mice and conditional knockout Mice have clarified the important role of Calhm2 in the activation of microglia, providing an important target for targeting microglia activation and neuroinflammation (Figure 7)
.
In addition, Calhm2 mediates calcium influx in microglia, and Calhm2 can interact with P2X7.
Calhm2 knockout significantly inhibits the function of P2X7, suggesting that Calhm2-mediated calcium homeostasis plays a key role in microglia activation
.
However, the mechanism of the up-regulation of Calhm2 in AD patients and AD model animals is still unclear.
In addition, the mechanism of Calhm2's regulation of P2X7 is also in urgent need of in-depth study
.
In conclusion, this study further enriches and expands the calcium homeostasis theory in the AD field, reveals the molecular mechanism of neuroinflammation, and provides potential intervention strategies for targeted neuroinflammation treatment of AD (Figure 7)
.
Original link: https://advances.
sciencemag.
org/content/7/35/eabe3600 The corresponding author of the paper is Associate Professor Cheng Jinbo of the Minzu University of China, and Researcher Yuan Zengqiang of the Academy of Military Medicine
.
The first author is Associate Professor Cheng Jinbo from Minzu University of China, and Dr.
Dong Yuan from Qingdao University.
This work was greatly assisted by Professor Yu Ye from Shanghai Jiaotong University and Dr.
Wang Liang from the Institute of Microbiology, Chinese Academy of Sciences
.
This work was jointly funded by key projects of the National Natural Science Foundation of China and general projects
.
Selected articles from previous issues [1] New Discovery of EMBO J︱! AGHGAP11B promotes the expansion of the neocortex into adulthood and improves cognitive ability [2] Cell Death Differ︱ Qi Yitao/Wu Hongmei and others cooperate to reveal the molecular mechanism of SUMO modification regulating neurogenesis in adult mice [3] Cereb Cortex︱A2A receptor antagonist can Reversing the sequence learning impairment induced by abnormal aggregation of α-Syn [4] Neuron︱Nicotine promotes the new discovery of anxiety-the important role of inhibiting the ventral tegmental area-amygdala dopamine pathway [5] Int J Mol Sci︱ Frontier review Interpretation: Pathophysiological response and role of astrocytes in traumatic brain injury [6] Cereb Cortex | Wang Lang's research group revealed that astrocytes have experience-dependent steady-state plasticity [7] New discovery in Nature︱! The social spread of maternal behavior caused by oxytocin neurons [8] Genome Biol︱ Ding Junjun’s team systematically draws a three-dimensional structure map of chromatin during phase separation, dissolution and reconstruction [9] New Brain︱ method! Plasma astrocyte proliferation GFAP or a new potential marker for Alzheimer’s disease detection [10] Autophagy︱Zhang Zhidong’s team reveals a new mechanism for STING1 to induce autophagy to regulate RNA virus infection [11] Nature︱ Astrocytes Source IL-3 regulates the function of microglia, relieves AD pathological changes and cognitive impairment [12] JCI︱ Gao Tianming’s research group reveals that the prefrontal cortex has an opposite role in regulating anxiety and fear in the neural circuit [13] eLife︱ Single cell sequencing and neural circuit analysis jointly reveal the molecular genetic coding mechanism of brain initiation of attack/defense instincts [14] Nature︱Frontier! GluDs transduce different pre-synaptic signals to different post-synaptic receptor responses.
References (Swipe up and down to view) [1] Khachaturian, ZS, Calcium, membranes, aging, and Alzheimer's disease.
Introduction and overview.
Ann NY Acad Sci, 1989.
568: p.
1-4.
[2] Alzheimer's Association Calcium Hypothesis, W .
,
