Nature: I never thought that fat is the "accomplice" of inflammatory astrocytes to kill neurons

Click on the blue letters to pay attention to our astrocytes when the central nervous system is injured, they are activated from a static state to form reactive astrocyte hyperplasia.
If the damage is severe, it will form a glial scar
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In disease states, astrocytes also exhibit this activation
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Reactive astrocytes can be further subdivided into type A1 (high expression of complement signaling pathway genes) and type A2 (high expression of multiple neurotrophic factors)
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Type A1 astrocytes lose most of their normal astrocyte functions, but gain new neurotoxic functions, quickly killing neurons and mature differentiated oligodendrocytes
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In the neuroimmune state, interleukin-1, tumor necrosis factor, and complement C1q derived from microglia can activate type A1 astrocytes
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However, another secretion may cause neurotoxicity of astrocytes: superoxide dismutase-1 (SOD1) mutations cause amyotrophic lateral sclerosis (ALS)
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Astrocytes expressing mutant SOD1 kill primary spinal cord neurons and motor neurons derived from embryonic mouse stem cells, which are mediated by soluble toxic factors
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On October 6, 2021, the Shane A.
Liddelow research team at the Institute of Neuroscience, New York University School of Medicine revealed that the soluble toxic factors secreted by astrocytes are saturated fatty acids
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The researchers used protein profiling technology to identify the protein composition of the medium containing reactive glial cells.
3660 kinds of proteins were detected in the presence of 176 protein-enriched expressions, of which the content of complement C3 is the most, and the expression of lipoproteins APOE and APOJ is also More
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Further separation through purification column found that complement C3 protein and lipoprotein APOE and APOJ have typical toxicity characteristics
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This indicates that the lipid particles secreted by astrocytes can serve as potentially toxic carriers
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After the expression of APOE and APOJ in inflammatory astrocytes is reduced, the toxicity is also reduced.
In vitro experiments have found that after depleting the lipoproteins APOE and APOJ on reactive astrocytes, these glial cells are no longer toxic
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However, astrocytes derived from APOE or APOJ knockout mice still have the ability to acquire toxicity, which indicates that lipoproteins are not toxic
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Subsequent further purification of the separated lipids from the medium containing reactive glial cells is toxic
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In addition, the cell membrane fragments of these reactive astrocytes are also toxic
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In order to further clarify the composition of these toxic lipids, they further found through lipidomics and metabolomics that the expression of phosphatidylcholine with very long fatty acid acyl chains (VLCPC) on reactive astrocyte membranes was significantly up-regulated , The expression of long-chain saturated free fatty acids (FFA) increased in the medium containing reactive glial cells
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After specifically knocking out the saturated lipid synthase ELOVL1 of astrocytes, the toxicity of reactive astrocytes was reduced
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Lipid toxicity can occur in the lipid peroxidation products formed during the lipid peroxidation process, which can change the stability of cell membranes and cause changes in cell structure and function.
It can also lead to the formation of reactive lipids and promote metabolism through non-oxidative pathways.
Related programmed cell death (lipid death)
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Saturated fatty acids cause cell death signaling pathways.
Researchers have found that lipid peroxidation inhibitors or antioxidant ethoxyquinolines do not affect the lipid-driven cytotoxicity of astrocytes, which indicates this lipid toxicity It is not the toxicity caused by lipid oxidation
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In adipocyte apoptosis, saturated lipids activate the PERK (protein kinase R-like endoplasmic reticulum kinase) endoplasmic reticulum stress response pathway, and upregulate the apoptosis regulator PUMA to induce cell death through P53
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After oligodendrocytes are cultured in a medium containing reactive glial cells, the expression of PUMA increases and caspase-3 is lysed, which indicates that the apoptosis signal pathway of adipocytes is enhanced
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The oligodendrocytes knocked out PUMA will not be infested by the toxic components of astrocytes
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In summary, this article uses multiple omics techniques to reveal that lipids secreted by astrocytes drive the lipid death of neurons and oligodendrocytes, and further reveal the neurotoxicity of reactive astrocytes.
Mechanism
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[References] https://doi.
org/10.
1038/s41586-021-03960-y The pictures in the text are from the references