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The APOE4 (apolipoprotein E4) gene is most associatedwith a genetic risk of AD (Alzheimer's disease).
The APOE4 allele is present in 40-50% of AD patients
.
APOE4 is associated with
increased amyloid β deposition, tau hyperphosphorylation and aggregation, and cognitive decline.
APOE is a lipid and cholesterol transporter
.
APOE4 polymorphisms alter the accessibility of lipid-binding regions, thereby interfering with cholesterol and lipid transport capacity
.
On November 16, 2022, a research team of Li-Huei Tsai, director of the Picow Institute for Learning and Memory at MIT, revealed that APOE4 impairs the formation of neuronal myelination through oligodendrocytes cholesterol aggregation, causing cognitive dysfunction
.
Single-cell transcriptomics of autopsy human brain tissues from APOE4 non-carriers and APOE4 carriers found that upregulation of inflammation and immune-related signals in multiple cell types of the brain was associated with APOE4: NF-кB signaling pathways in excitatory neurons, suppressor neurons, and OPCs (oligodendrocytes precursor cells); T cell receptors and cytokine signaling pathways in astrocytes; Microglia and excitatory neuronal tumor necrosis factor-mediated signaling pathways
.
Ion-channel activity, excitatory postsynaptic potential, and synaptic plasticity are downregulated
by synaptic-related signaling pathways.
APOE4 is implicated
in cellular stress and energy metabolism in multiple cell types.
ATF-mediated unfolded protein responses are increased
in neurons and oligodendrocytes.
APOE4 cholesterol biosynthesis signaling was increased in oligodendrocyte, lipid storage in OPCs, and glycogen metabolism in microglia and astrocytes, while acetyl-CoA metabolism signaling was decreased
in astrocytes.
Figure 1; APOE4 alters oligodendrocyte cholesterol homeostatic signaling
Further analysis found that APOE4 significantly altered the signaling pathways associated with cholesterol homeostasis and transport: increased gene expression related to cholesterol biosynthesis and lipid droplet formation, and down-regulationof gene expression related to cholesterol transport.
Immunofluorescence experiments showed that there were increased
cholesterol and lipid droplets in the cortical tissues of APOE4 carriers.
Further experiments found that this increase in cholesterol and lipid droplets was cell-specific: the increase was more pronounced
in oligodendrocytes.
In the central nervous system, neuronal myelin sheaths are formed by oligodendrocytes, and the bioavailability of cholesterol limits the formation and maintenance
of myelin.
Therefore, the abnormal increase of cholesterol and lipid droplets in oligodendrocyte caused by APOE4 above may affect the formation of myelin sheath, and the downregulation of cerebral myelin-related genes carrying APOE4 gene loci and reduced myelination formation; In addition, the density of cortical myelin sheath carrying the APOE4 gene was significantly reduced, and the degree of myelination of neurons was also significantly reduced
.
These results suggest that the expression of APOE4 in oligodendrocytes promotes cholesterol accumulation and impaired
myelination formation.
Figure 2: Expression of APOE4 in oligodendrocytes causes impaired
myelination.
of cholesterol.
In oligodendrocyte and neuronal co-culture systems carrying the APOE4 gene, neuronal myelination was significantly reduced, but myelination could be significantly increased after cyclodextrin treatment
.
APOE4/4 mice had significantly reduced cholesterol aggregation and myelination in hippocampal tissues after cyclodextrin injection
.
In addition, multiple injections of cyclodextrin were able to significantly improve cognitive function
in APOE4/4 mice.
Figure 3; Improves cognitive function after reducing cholesterol accumulation in the brain
In this paper, APOE4 significantly alters oligodendrocyte lipid and cholesterol homeostasis in the human brain, and this homeostatic imbalance causes a decrease in myelination formation, which can significantly improve cognitive function
after correcting this disorder.
【References】
1.
https://doi.
org/10.
1038/s41586-022-05439-w
The images in the article are from references
