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Life sciences Life science recently, the team of Professor Liu Qiang from the University of Science and Technology of China published a research paper entitled "Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory" in Neuron magazine, revealing the origin of astrocytes The mechanism by which ApoE reprograms the cholesterol metabolism of neurons, and the effect of this metabolic regulation on neuronal function, especially the process of learning and memory.
▲Long press the picture to identify the two-dimensional code to read the original text.
Astrocytes are the most widely distributed type of cells in the mammalian brain, and they are also the largest type of glial cells.
Apolipoprotein E (ApoE) produced by astrocytes is one of the most abundant apolipoproteins in the brain.
Together with cholesterol and other lipids, it forms a cholesterol-rich high-density lipoprotein complex, and is composed of ApoE particles.
The form is secreted out of glial cells, and then taken up and used by neurons through ApoE receptors.
Neurons synthesize very little cholesterol by themselves, but mainly rely on the cholesterol provided by the transcellular transport of ApoE lipids derived from glial cells.
However, how the neuronal cholesterol self-synthesis pathway is silenced and the effect of this metabolic reprogramming mechanism on neuronal function remains unclear.
Using high-throughput sequencing and metabolite tracking, Professor Liu Qiang's team found that ApoE derived from astrocytes significantly inhibited the expression of key synthase in the neuronal cholesterol synthesis pathway, thereby inhibiting neuronal cholesterol synthesis.
ApoE-mediated inhibition of cholesterol synthesis in neurons significantly accumulates the precursor of cholesterol synthesis in neurons: acetyl-CoA.
The study further found that ApoE can increase the level of histone acetylation related to transcription activation by up-regulating the level of acetyl-donor acetyl-CoA in neuronal nuclei.
The function of neurons, especially the realization of cognitive functions such as learning and memory, requires precise regulation of neuronal gene expression, and the epigenetic regulation mechanism, especially histone acetylation, is closely related to this process.
The study showed that ApoE regulates the transcription of early response genes by regulating the level of acetylated histones in the promoter region.
Through the analysis of the components of ApoE particles, it is found that ApoE's metabolic regulation of neurons depends on the miRNA carried by it.
These miRNAs can specifically bind to the 3'UTR sequences of multiple cholesterol synthases, thereby down-regulating these synthesis.
Enzyme levels.
The important thing is that ApoE-mediated neuronal metabolism and epigenetic regulation shows obvious subtype specificity, and ApoE4's ability to regulate neuronal cholesterol metabolism and epigenetic regulation is significantly weaker than ApoE3.
Under the same fear memory stimulation paradigm, compared with ApoE3 mice, the levels of acetyl-CoA and histone acetylation in the brains of ApoE4 mice have been significantly reduced, and the levels of early response genes are also significantly down-regulated.
These results reveal that ApoE4 participates in the pathological process of Alzheimer's disease through regulation of neuronal metabolism and epigenetics.
This study reveals for the first time the brand-new functions of ApoE in the brain, elucidating a new mechanism by which ApoE derived from astrocytes affects learning and memory by regulating neuronal cholesterol metabolism and epigenetic processes.
It also explains how ApoE4 acts as a The high-risk factors of Alzheimer's disease are involved in the disease process, which is of great significance for deep understanding of the pathogenesis of Alzheimer's disease.
The following is a schematic diagram of the article.
The postdoctoral fellows of Liu Qiang's research group Li Xiaohui and Zhang Juan are the first authors of this article, and Professor Liu Qiang is the corresponding author.
The research was funded by the Ministry of Science and Technology, the Chinese Academy of Sciences, and the National Natural Science Foundation of China.
It also received strong support from the Anhui Provincial Natural Science Foundation and the University of Science and Technology of China. The author's interview with Cell Press Cell Press specially invited Professor Liu Qiang, the corresponding author of the paper, for an exclusive interview, and asked him to further explain it in detail.
CellPress: First of all, please introduce the background of this research.
Professor Liu Qiang: Astrocytes are the most widely distributed type of cells in the mammalian brain, and they are also the largest type of glial cells.
Apolipoprotein E (ApoE) produced by astrocytes is one of the most abundant apolipoproteins in the brain.
Together with cholesterol and other lipids, it forms a cholesterol-rich high-density lipoprotein complex, and is composed of ApoE particles.
The form is secreted out of glial cells, and then taken up and used by neurons through ApoE receptors.
The ability of neurons to synthesize cholesterol is weak, but mainly depends on cholesterol derived from glial cells, which is transported by ApoE-mediated lipids across cells.
However, how the neuronal cholesterol self-synthesis pathway is silenced and the effect of this metabolic reprogramming mechanism on neuronal function remains unclear.
It is unclear whether ApoE derived from glial cells may participate in the metabolic reprogramming process of neurons.
Therefore, this research conducted an in-depth study based on these issues.
CellPress: How do ApoE particles cause the accumulation of acetyl-CoA in neuronal cells? Professor Liu Qiang: Using high-throughput sequencing methods, it was found that after ApoE particles secreted by astrocytes enter cells through ApoE receptors on neurons, they significantly inhibit the expression of cholesterol synthase in neurons, using metabolite tracking methods It was found that this inhibitory mechanism resulted in the accumulation of acetyl-CoA, the precursor of cholesterol synthesis, in the cell, revealing that ApoE derived from astrocytes inhibits the expression of the neuron’s own cholesterol synthase, resulting in acetyl-CoA in neuronal cells.
Accumulation within.
CellPress: How does ApoE affect histone acetylation in neurons, thereby affecting the learning and memory process? Professor Liu Qiang: Acetyl-CoA is the precursor of cholesterol synthesis.
The study found that ApoE significantly accumulates the level of its precursor acetyl-CoA by inhibiting the synthesis of cholesterol, especially the level of acetyl-CoA in the nucleus has a significant increase. The acetyl-CoA in the nucleus is an important donor of the acetyl group in the process of histone acetylation.
Further studies have found that ApoE can significantly increase the acetylation levels of K9 and K27 of histone H3, and K5 and K12 of histone H4.
The acetylation of these histone lysine sites is closely related to the activation of transcription.
.
The function of neurons, especially the realization of cognitive functions such as learning and memory, requires precise regulation of gene expression, and the epigenetic regulation mechanism, especially histone acetylation, is closely related to this process.
Using astrocyte ApoE knockdown mice for fear memory stimulation, it was found that compared with control mice, the levels of acetyl-CoA and histone acetylation were significantly reduced in the brains of ApoE knockdown mice, and at the same time early response genes The level has also dropped significantly.
At the same time, the level of H3K27 acetylation in the promoter region of these early response genes was significantly reduced, indicating that ApoE regulates the transcription of early response genes by regulating the level of acetylated histones in the promoter region, thereby participating in the regulation of learning and memory processes.
.
CellPress: What kind of RNA is enriched in ApoE particles, and why did you choose miR-126 for further research? Professor Liu Qiang: When analyzing the RNA components of ApoE particles, we found that the RNA is mainly a small RNA molecule with a length of 20-22 nucleotides, that is, miRNA.
After analyzing the miRNA expression of ApoE particles, it was found that many highly abundant miRNAs can bind to the 3'UTR sequences of multiple cholesterol synthase.
miR-126 is not only highly enriched in ApoE particles, but also highly conserved among different species, thus becoming the target of this research.
ApoE particles derived from glial cells overexpressed miR-126 can significantly inhibit the cholesterol synthesis pathway in neurons, and significantly increase the acetylation levels of acetyl-CoA and histones, further confirming that ApoE particles are carried by miRNAs.
Participate in regulatory functions. CellPress: Why can ApoE enhance the effect of memory consolidation in an isotype-specific way? Professor Liu Qiang: There are obvious differences in the levels of miRNA carried by different ApoE subtypes.
The level of miRNA carried by ApoE4 is relatively low, so its ability to regulate neuronal cholesterol metabolism and epigenetics is relatively weak.
Under the same fear memory stimulation paradigm, compared with ApoE3 mice, the levels of acetyl-CoA and histone acetylation in the brains of ApoE4 mice have been significantly reduced, and the levels of early response genes are also significantly down-regulated.
These results explain the difference in cognitive behavior of different subtypes of ApoE mice.
CellPress: What implications does this study have for the treatment of cognitive decline related to aging or neurodegenerative diseases? Professor Liu Qiang: ApoE4 is an important risk factor for neurodegenerative diseases such as brain aging and Alzheimer's disease, and cognitive decline is one of the important phenotypes of aging and related degenerative changes.
This research is of great significance for understanding how ApoE4, as a high-risk factor of Alzheimer's disease, participates in the regulation of cognitive function, and for in-depth understanding of the pathogenesis of Alzheimer's disease.
At the same time, this research also provides a potential therapeutic target for the treatment of Alzheimer's disease.
The research results of related paper information are published in Neuron journals under Cell Press.
Click "Read Full Text" or scan the QR code below to view the papers.
▌Paper title: Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory▌Paper URL: https://▌DOI: https:/ /doi.
org/10.
1016/j.
neuron.
2021.
01.
005▲Long press the picture to identify the QR code to read the original textRecommend to read the Neuron 2019-2020 Best Paper Special Issue▲
▲Long press the picture to identify the two-dimensional code to read the original text.
Astrocytes are the most widely distributed type of cells in the mammalian brain, and they are also the largest type of glial cells.
Apolipoprotein E (ApoE) produced by astrocytes is one of the most abundant apolipoproteins in the brain.
Together with cholesterol and other lipids, it forms a cholesterol-rich high-density lipoprotein complex, and is composed of ApoE particles.
The form is secreted out of glial cells, and then taken up and used by neurons through ApoE receptors.
Neurons synthesize very little cholesterol by themselves, but mainly rely on the cholesterol provided by the transcellular transport of ApoE lipids derived from glial cells.
However, how the neuronal cholesterol self-synthesis pathway is silenced and the effect of this metabolic reprogramming mechanism on neuronal function remains unclear.
Using high-throughput sequencing and metabolite tracking, Professor Liu Qiang's team found that ApoE derived from astrocytes significantly inhibited the expression of key synthase in the neuronal cholesterol synthesis pathway, thereby inhibiting neuronal cholesterol synthesis.
ApoE-mediated inhibition of cholesterol synthesis in neurons significantly accumulates the precursor of cholesterol synthesis in neurons: acetyl-CoA.
The study further found that ApoE can increase the level of histone acetylation related to transcription activation by up-regulating the level of acetyl-donor acetyl-CoA in neuronal nuclei.
The function of neurons, especially the realization of cognitive functions such as learning and memory, requires precise regulation of neuronal gene expression, and the epigenetic regulation mechanism, especially histone acetylation, is closely related to this process.
The study showed that ApoE regulates the transcription of early response genes by regulating the level of acetylated histones in the promoter region.
Through the analysis of the components of ApoE particles, it is found that ApoE's metabolic regulation of neurons depends on the miRNA carried by it.
These miRNAs can specifically bind to the 3'UTR sequences of multiple cholesterol synthases, thereby down-regulating these synthesis.
Enzyme levels.
The important thing is that ApoE-mediated neuronal metabolism and epigenetic regulation shows obvious subtype specificity, and ApoE4's ability to regulate neuronal cholesterol metabolism and epigenetic regulation is significantly weaker than ApoE3.
Under the same fear memory stimulation paradigm, compared with ApoE3 mice, the levels of acetyl-CoA and histone acetylation in the brains of ApoE4 mice have been significantly reduced, and the levels of early response genes are also significantly down-regulated.
These results reveal that ApoE4 participates in the pathological process of Alzheimer's disease through regulation of neuronal metabolism and epigenetics.
This study reveals for the first time the brand-new functions of ApoE in the brain, elucidating a new mechanism by which ApoE derived from astrocytes affects learning and memory by regulating neuronal cholesterol metabolism and epigenetic processes.
It also explains how ApoE4 acts as a The high-risk factors of Alzheimer's disease are involved in the disease process, which is of great significance for deep understanding of the pathogenesis of Alzheimer's disease.
The following is a schematic diagram of the article.
The postdoctoral fellows of Liu Qiang's research group Li Xiaohui and Zhang Juan are the first authors of this article, and Professor Liu Qiang is the corresponding author.
The research was funded by the Ministry of Science and Technology, the Chinese Academy of Sciences, and the National Natural Science Foundation of China.
It also received strong support from the Anhui Provincial Natural Science Foundation and the University of Science and Technology of China. The author's interview with Cell Press Cell Press specially invited Professor Liu Qiang, the corresponding author of the paper, for an exclusive interview, and asked him to further explain it in detail.
CellPress: First of all, please introduce the background of this research.
Professor Liu Qiang: Astrocytes are the most widely distributed type of cells in the mammalian brain, and they are also the largest type of glial cells.
Apolipoprotein E (ApoE) produced by astrocytes is one of the most abundant apolipoproteins in the brain.
Together with cholesterol and other lipids, it forms a cholesterol-rich high-density lipoprotein complex, and is composed of ApoE particles.
The form is secreted out of glial cells, and then taken up and used by neurons through ApoE receptors.
The ability of neurons to synthesize cholesterol is weak, but mainly depends on cholesterol derived from glial cells, which is transported by ApoE-mediated lipids across cells.
However, how the neuronal cholesterol self-synthesis pathway is silenced and the effect of this metabolic reprogramming mechanism on neuronal function remains unclear.
It is unclear whether ApoE derived from glial cells may participate in the metabolic reprogramming process of neurons.
Therefore, this research conducted an in-depth study based on these issues.
CellPress: How do ApoE particles cause the accumulation of acetyl-CoA in neuronal cells? Professor Liu Qiang: Using high-throughput sequencing methods, it was found that after ApoE particles secreted by astrocytes enter cells through ApoE receptors on neurons, they significantly inhibit the expression of cholesterol synthase in neurons, using metabolite tracking methods It was found that this inhibitory mechanism resulted in the accumulation of acetyl-CoA, the precursor of cholesterol synthesis, in the cell, revealing that ApoE derived from astrocytes inhibits the expression of the neuron’s own cholesterol synthase, resulting in acetyl-CoA in neuronal cells.
Accumulation within.
CellPress: How does ApoE affect histone acetylation in neurons, thereby affecting the learning and memory process? Professor Liu Qiang: Acetyl-CoA is the precursor of cholesterol synthesis.
The study found that ApoE significantly accumulates the level of its precursor acetyl-CoA by inhibiting the synthesis of cholesterol, especially the level of acetyl-CoA in the nucleus has a significant increase. The acetyl-CoA in the nucleus is an important donor of the acetyl group in the process of histone acetylation.
Further studies have found that ApoE can significantly increase the acetylation levels of K9 and K27 of histone H3, and K5 and K12 of histone H4.
The acetylation of these histone lysine sites is closely related to the activation of transcription.
.
The function of neurons, especially the realization of cognitive functions such as learning and memory, requires precise regulation of gene expression, and the epigenetic regulation mechanism, especially histone acetylation, is closely related to this process.
Using astrocyte ApoE knockdown mice for fear memory stimulation, it was found that compared with control mice, the levels of acetyl-CoA and histone acetylation were significantly reduced in the brains of ApoE knockdown mice, and at the same time early response genes The level has also dropped significantly.
At the same time, the level of H3K27 acetylation in the promoter region of these early response genes was significantly reduced, indicating that ApoE regulates the transcription of early response genes by regulating the level of acetylated histones in the promoter region, thereby participating in the regulation of learning and memory processes.
.
CellPress: What kind of RNA is enriched in ApoE particles, and why did you choose miR-126 for further research? Professor Liu Qiang: When analyzing the RNA components of ApoE particles, we found that the RNA is mainly a small RNA molecule with a length of 20-22 nucleotides, that is, miRNA.
After analyzing the miRNA expression of ApoE particles, it was found that many highly abundant miRNAs can bind to the 3'UTR sequences of multiple cholesterol synthase.
miR-126 is not only highly enriched in ApoE particles, but also highly conserved among different species, thus becoming the target of this research.
ApoE particles derived from glial cells overexpressed miR-126 can significantly inhibit the cholesterol synthesis pathway in neurons, and significantly increase the acetylation levels of acetyl-CoA and histones, further confirming that ApoE particles are carried by miRNAs.
Participate in regulatory functions. CellPress: Why can ApoE enhance the effect of memory consolidation in an isotype-specific way? Professor Liu Qiang: There are obvious differences in the levels of miRNA carried by different ApoE subtypes.
The level of miRNA carried by ApoE4 is relatively low, so its ability to regulate neuronal cholesterol metabolism and epigenetics is relatively weak.
Under the same fear memory stimulation paradigm, compared with ApoE3 mice, the levels of acetyl-CoA and histone acetylation in the brains of ApoE4 mice have been significantly reduced, and the levels of early response genes are also significantly down-regulated.
These results explain the difference in cognitive behavior of different subtypes of ApoE mice.
CellPress: What implications does this study have for the treatment of cognitive decline related to aging or neurodegenerative diseases? Professor Liu Qiang: ApoE4 is an important risk factor for neurodegenerative diseases such as brain aging and Alzheimer's disease, and cognitive decline is one of the important phenotypes of aging and related degenerative changes.
This research is of great significance for understanding how ApoE4, as a high-risk factor of Alzheimer's disease, participates in the regulation of cognitive function, and for in-depth understanding of the pathogenesis of Alzheimer's disease.
At the same time, this research also provides a potential therapeutic target for the treatment of Alzheimer's disease.
The research results of related paper information are published in Neuron journals under Cell Press.
Click "Read Full Text" or scan the QR code below to view the papers.
▌Paper title: Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory▌Paper URL: https://▌DOI: https:/ /doi.
org/10.
1016/j.
neuron.
2021.
01.
005▲Long press the picture to identify the QR code to read the original textRecommend to read the Neuron 2019-2020 Best Paper Special Issue▲
