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Written by | Qi
Genome-wide association studies have identified genetic variants associated with an increased risk of AD (Alzheimer's disease), with APOE4 showing the strongest association with increased β amyloid deposition, excessive phosphorylation and aggregation of tau proteins, and accelerated cognitive decline, but the mechanism by which APOE4 mediates these alterations is not fully understood 【1-3】
。 As a lipid and cholesterol transporter, APOE4 polymorphisms alter the accessibility of lipid-binding regions, thereby interfering with cholesterol and lipid transport, but how abnormalities in this function impair learning and memory and whether this effect can be mitigated by some pathway is unclear
.
On November 16, 2022, the Li-Huei Tsai team from MIT and the Manolis Kellis team collaborated to publish the article APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes in the journal Nature
。 They performed single-cell transcriptomic analysis of autopsy human brains of APOE4 carriers versus non-carriers, which significantly altered signaling pathways
associated with cholesterol homeostasis and transport.
These findings were confirmed by histological and lipidomic analysis of autopsies of the human brain, induced pluripotent stem cell-derived cells, and targeted replacement mice, namely abnormal deposition of cholesterol in oligodendrocytes
.
Pharmacology promotes cholesterol transport, increases axonal myelination and improves learning and memory
in APOE4 mice.
Together, this work provides a single-cell atlas describing the transcriptional effects of APOE4 on aging human brains and establishing functional links between APOE4, cholesterol, myelination, and memory, providing therapeutic opportunities
for AD.
The researchers first performed snRNA-seq and differential pathway analysis from autopsy prefrontal cortex (PFC) samples from APOE3/3, APOE3/4, and APOE4/4 carriers.
Upregulation of inflammatory and immune-related pathways encompassing multiple cell types, downregulation of synaptic-related processes (e.
g.
, ion channel activity, synaptic plasticity, etc.
), and alterations
in lipid metabolism-related processes were identified.
It is important to note that genes associated with cholesterol biosynthesis and droplet formation are upregulated in oligodendrocytes, while genes associated with cholesterol transport are down-regulated
.
The researchers then performed mass spectrometry-based lipidomics analysis of autopsy brain tissue, and APOE4/4 individuals showed a trend
towards higher levels of cholesterol esters.
Because genetic diversity can confound the effects of APOE4 on human postmortem brain tissue, the authors used APOE3/3 and APOE4/4 iPS cells generated by CRISPR-dCas9 editing, which subsequently differentiated into oligodendrocytes
.
Similar to autopsy oligodendrocytes, cholesterol esters were the most altered lipid class, and BODIPY-cholesterol staining and PLIN1 immune response showed high overlap, suggesting that APOE4/4 increased cholesterol storage
within oligodendrocytes.
In addition, APOE4/4 oligodendrocytes exhibited ATF6-mediated upregulation of the ER stress pathway, with increased expression of multiple heat shock proteins and ATF6, a key regulator of the unfolded protein response.
At the same time, multiple genes associated with ER cholesterol transport were downregulated in APOE4/4 oligodendrocytes, suggesting that ER stress and impaired cholesterol transport may play a central role
in the observed intracellular cholesterol accumulation.
Oligodendrocytes are associated with myelination in the central nervous system, and the researchers theorize that alterations in cholesterol localization and homeostasis in APOE4/4 oligodendrocytes may impair myelination
.
To verify this, the authors examined myelin-related genes and myelin immunostaining in turn, observed myelinated axons in the brains of APOE4/4-TR mice, and demonstrated them by in vitro myelination assays (iPS-derived oligodendrocytes and neuronal co-culture).
Then pharmacologically inhibit cholesterol biosynthesis (simvastatin and atorvastatin) in APOE4/4 oligodendrocytes or promote cholesterol transport (2-hydroxypropyl-β-cyclodextrin; Cyclodextrin) to reduce intracellular accumulation improve myelination? To this end, the authors treated APOE4/4 iPS cell-derived oligodendrocytes with these drugs to quantify intracellular cholesterol by BODIPY-cholesterol staining, while the authors also treated co-cultured APOE4/4 oligodendrocytes and neurons with drugs to assess the myelination phenotype
.
The above test results, combined with observations from mouse models, together suggest that pharmacological enhancement of cholesterol transport can improve myelination
in vitro and in vivo.
Finally, to investigate whether the increased myelination observed in cyclodextrin-treated APOE4/4-TR mice is associated with improved function, the authors assessed learning and memory capacity
using novel object recognition analysis.
Total travel distance and time spent in the center of the open field indicate that cyclodextrin treatment does not affect general movement or induce anxiety-like behavior, and that APOE4/4-TR mice treated with cyclodextrin have a significantly increased preference for new objects compared to control mice when exposed to new objects
.
In addition, the authors used the labyrinth experiment (a test used to assess demyelinating-related cognitive dysfunction) to conduct additional assessments of learning and executive function, and the results also showed that cyclodextrin treatment can improve learning and executive function
in elderly APOE4/4-TR mice.
In conclusion, this work demonstrates that cholesterol transport may be an entry point for pharmacatively targeted impaired myelination and that promoting cholesterol transport can increase myelination in APOE4/4 mice and improve cognitive function
.
By establishing mechanistic links between APOE4, cholesterol transport and oligodendrocytes localization, myelin damage, and cognitive ability, AD offers therapeutic opportunities
.
Original link:
https://doi.
org/10.
1038/s41586-022-05439-w
Platemaker: Eleven
References
1.
Lambert, J.
C.
et al.
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease.
Nat.
Genet.
45, 1452–1458 (2013).
2.
Corder, E.
H.
et al.
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.
Science 261, 921–923 (1993).
3.
Strittmatter, W.
J.
et al.
Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
Proc.
Natl Acad.
Sci.
USA 90, 1977–1981 (1993).
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