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Written | Yan Xiao Astrocytes are located between the cell bodies of nerve cells and their processes.
They support and guide neurons, enhance the survival of neurons, and promote synaptic connections between neurons.
They are the most widely distributed in the brain.
Class cell
.
Studies have shown that astrocytes not only have a neuroprotective effect, but are also the culprit of certain neurological diseases: astrocytes will undergo functional changes when dealing with central nervous system (Central nervous system, CNS) diseases and injuries, such as Traumatic brain injury, infection and other diseases can transform "good" "resting astrocytes" into abnormal "reactive astrocytes"; in brain injury and some neurological diseases (such as Alzheimer's disease) Abundant abnormal state of astrocytes have also been found in brain tissue samples from patients with Murr's disease, Parkinson’s disease and multiple sclerosis.
Studies have suggested that these glial cells will kill neurons.
The specific mechanism is still Not sure
.
Although the current development of drugs for neurological diseases is mainly aimed at neurons, many neurological diseases can also be treated by blocking the mutation of astrocytes or resisting the toxins secreted by astrocytes that kill neurons.
Therefore, exploring astrology The mechanism by which glial cells damage neurons is particularly important for drug development
.
On October 6, 2021, Ben A.
Barres' team from Stanford University in the United States and Shane A.
Liddelow's team from New York University School of Medicine published a research paper entitled Neurotoxic reactive astrocytes induce cell death via saturated lipids online in Nature.
Reveals a new mechanism to explain how astrocytes kill cells in the central nervous system
.
Previous studies have shown that the toxicity of reactive astrocytes is mediated by secreted proteins [1-2]
.
In order to identify specific toxic factors, the authors analyzed the changes in protein abundance in reactive glial cells and control (resting) glial cells and astrocyte conditioned medium (ACM) (Figure 1), and use mature oligodendrocytes to assess the toxicity of ACM
.
Mass spectrometry data showed that among the 3,660 proteins detected, 176 proteins were altered in reactive astrocytes
.
Regarding the secreted proteins in astrocytes, in addition to previously reported factors such as SPARC [3], the authors also observed changes in other factors in reactive ACM, such as C3, lipocalin-2, and other reactive markers.
[4]
.
Unexpectedly, toxicity evaluation experiments showed that these factors did not cause the death of oligodendrocytes, indicating that the true toxicity factors were not found
.
However, the author noticed that reactive ACM is rich in lipoproteins APOE and APOJ, suggesting that lipid metabolism in astrocytes may have changed
.
Figure 1.
Screening experiment design and process.
Subsequently, the author performed a more detailed separation and purification of ACM based on size, charge, and hydrophobicity, and evaluated the toxicity of each component
.
Mass spectrometry analysis found that the most significantly regulated protein category in the purified components was lipid granule proteins, such as APOE and APOJ, which once again indicated changes in astrocyte lipid metabolism, implying astrocyte secretion The lipid particles are potential carriers of toxicity
.
In order to further confirm the increase in lipid secretion, the authors performed enzyme-linked immunosorbent assays (ELISAs) to quantify the concentration of APOE and APOJ in resting and reactive ACM, and found that both lipoproteins are rich Set in reactive ACM
.
After using APOE and APOJ antibodies to remove lipids from resting and reactive ACM, the toxicity of ACM was significantly reduced, indicating that APOE and APOJ lipid particles are necessary for astrocyte-mediated toxicity
.
So does lipoprotein or lipid content mediate the toxicity? First, the author explored whether APOE or APOJ protein itself is toxic
.
By collecting and analyzing Apoe-/-, Apoj-/- or Apoe-/-Apoj-/- mouse astrocyte ACM, it was found that the toxicity of these ACMs was consistent with that of the control group, and there was no significant difference, indicating that these lipids The protein itself is not toxic
.
On the contrary, when the Lipidex3000 column is used to remove the lipid in the reactive ACM, its toxicity is basically eliminated, revealing that the lipid itself is a necessary and sufficient condition for the toxicity of ACM
.
The authors used recombinant lipid particles (rHDL, containing lipids derived from activated ACM) to reproduce astrocyte-mediated toxicity: rHDL containing resting ACM lipids is non-toxic, while containing reactive ACM Lipid rHDL showed strong toxicity, indicating that the concentration of toxic lipids in reactive glial cells ACM was higher
.
Which lipid component in lipid particles is directly related to toxicity? The author performed lipidome and metabolome tests on cell extracts and ACM from resting and reactive glial cells (Figure 2)
.
Compared with resting glial cells, lipid metabolism in reactive glial cells has changed significantly, while the metabolome has only slight changes
.
It is worth noting that in reactive astrocyte membranes, phosphatidylcholine and very-long-chain fatty acid acyl chains (VLCPCs) are significantly upregulated; in reactive ACM, long-chain Saturated free fatty acids (FFAs) are significantly up-regulated
.
The content of these lipids in resting astrocyte membranes and lipid particles containing APOE and APOJ is usually relatively low.
Both lipids are toxic to oligodendrocytes, and the longer the lipid chain, the more toxic it is.
Big
.
Figure 2.
Experimental design and process of lipidomics and metabolomics.
Finally, the author explored whether the cell death mechanism initiated by reactive ACM is consistent with the toxicity mechanism mediated by long-chain saturated lipids
.
By Western blotting to detect changes in the lipid apoptosis pathway indicator protein, the authors found that in the oligodendrocytes treated with reactive ACM, the phosphorylation level of FOXO3A decreased, the expression of PUMA increased, and the caspase-3 cleavage increased
.
Only PUMA knockout (Bbc3-/-) oligodendrocytes are resistant to cell death caused by reactive ACM, indicating that PUMA is a key factor in the process of lipid apoptosis leading to cell death
.
The authors target ELOVL1 (a metabolic enzyme responsible for the synthesis of long-chain, fully saturated lipids (≥C16:0)) to eliminate the production of long-chain saturated lipids, proving their necessity for astrocyte-mediated toxicity
.
Elovl1flox/flox mice were bred with Gfap-cre mice, and Elovl1 astrocyte-specific knockout mice were obtained
.
Astrocytes were isolated from wild-type and Elovl1 knockout mice, and their lipid groups in the resting state and in the activated state were compared
.
Consistent with expectations, the authors observed that the abundance of long-chain saturated fatty acids in Elovl1 knockout cells was lower than that in the control group
.
Reactive ACM derived from Elovl1 knockout mice is also significantly less toxic to oligodendrocytes than wild-type mice
.
These results indicate that saturated lipids mediate the toxicity of reactive astrocytes, and Elovl1 knockout can reduce the production of these toxic lipids
.
In summary, the study found that saturated lipids rather than proteins contained in APOE and APOJ lipid particles mediate the toxicity caused by reactive astrocytes
.
By specifically knocking out the saturated lipid synthase ELOVL1 in astrocytes to eliminate the formation of long-chain saturated lipids, the toxicity caused by astrocytes can be reduced in vitro and in vivo acute axon injury models
.
These findings highlight the important role of astrocytes in responding to CNS damage and neurodegenerative diseases on the one hand, and reveal the function of lipids in CNS signal transduction on the other hand
.
Although a large part of the toxicity of reactive ACM is mediated by saturated lipids, reducing these lipids cannot completely eliminate neurotoxicity, indicating that there are other mechanisms that remain to be elucidated
.
The author believes that future research work will be expected to outline many lipid-mediated signaling pathways in the brain, and explore the therapeutic potential of inhibiting the secretion of toxic lipids and lipid apoptosis in diseases and injuries
.
Original link: https://doi.
org/10.
1038/s41586-021-03960-y Platemaker: Eleven References [1] Nagai, M.
et al.
Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons.
Nat.
Neurosci.
10, 615–622 (2007).
[2] Giorgio, F.
, Carrasco, MA, Siao, MC, Maniatis, T.
& Eggan, K.
Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell–based ALS model.
Nat.
Neurosci.
10, 608–614 (2007).
[3] Kucukdereli, H.
et al.
Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC.
Proc.
Natl Acad.
Sci.
USA 108, E440–E449 (2011).
[4] Bi, F.
et al.
Reactive astrocytes secrete lcn2 to promote neuron death.
Proc.
Natl Acad.
Sci.
USA 110, 4069–4074 (2013).
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