AD literature reading: Nature—APOE4 drives myelin damage by inducing dysphenidrocytes cholesterol metabolism

Chinese summary

APOE4 is the strongest genetic risk factor
for Alzheimer's disease.
However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutic drugs for individuals carrying APOE4 and other risk factors for Alzheimer's disease
.
Here, in order to understand the effects of APOE4 on the human brain more fully, the researchers conducted single-cell transcriptomic analysis of postmortem human brain tissues of APOE4 carriers and non-carriers, and found that APOE4 was associated with
a wide range of gene expression changes in all cell types in the human brain.
Consistent with the biological function of APOE, APOE4 significantly alters signaling pathways
associated with cholesterol homeostasis and transport.
They confirmed these findings through histological and lipidomic analysis of postmortem human brains, induced pluripotent stem cell-derived cells, and targeted replacement mice, with abnormal cholesterol deposited in
myelinocytes that maintain insulation and promote neuronal electrical activity.
They found that alterations in the localization of cholesterol in the APOE4 brain coincided with
a decrease in myelination formation.
Pharmacological promotion of cholesterol transport increases axonal myelination in APOE4 mice and improves learning and memory
.
Therefore, the scientists provided a single-cell atlas to describe the transcriptional regulatory role of APOE4 on the aging human brain, and established a functional link between APOE4, cholesterol, myelination and memory, providing a therapeutic strategy
for Alzheimer's disease.

Summary in English

APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3.
However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for inpiduals carrying APOE4 and other risk factors for Alzheimer's disease4-8.
Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers.
This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain.
Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport.
Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons.
We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination.
Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice.
We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.

References: APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.
Nature.
2022 Nov 16.
doi: 10.
1038/s41586-022-05439-w.

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