Nature: revealed that the APOE4 gene causes lipid dysregulation in oligodendrocytes, destroying neuronal myelination, thereby increasing the risk of Alzheimer's disease

It is known that carrying one copy of the APOE4 gene variant triples a person's risk of developing Alzheimer's disease, and carrying two copies of it increases that risk about tenfold, but the underlying cause and what can be done to help patients remains largely unknown
.
In a new study, researchers from the Massachusetts Institute of Technology in the United States offer some new answers as part of a broader study confirming the effects of
APOE4 on different cell types in the brain.
The findings were published online in Nature on November 16, 2022, under the title "APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.
"
The corresponding authors are Professor Li-Huei Tsai, director of MIT's Pikaul Institute for Learning and Memory, and Manolis Kellis, Ph.
D.
, professor of computer science at MIT.

The new study, which combines evidence from postmortem human brains, laboratory human brain cell cultures, and Alzheimer's disease model mice, shows that when people carry one or two copies of APOE4 instead of the more common, risk-neutral APOE3 gene variant, cells called oligodendrocytes incorrectly manage cholesterol and are unable to transport this fat molecule to wrap the long vine-like axon "circuits" projected by neurons to establish brain circuit connections
。 This lack of fat insulation called myelin may be an important factor in the pathology and symptoms of Alzheimer's disease, because without proper myelin, communication between neurons degenerates
.

Recent research by a research team led by Professor Li-Huei Tsai, director of MIT's Picaul Institute for Learning and Memory, has discovered how APOE4 disrupts the unique way
in which key brain cell types, including neurons, astrocytes and microglia, process fat molecules called lipids.
In this new study and those that preceded it, the team identified compounds in the lab that could correct these different problems, with the potential to develop drug-based therapeutic strategies
.

The new study not only expands on the previous one by discovering how APOE4 disrupts myelination, but also provides the first systematic analysis involving major brain cell types by using monocytes sequencing (snRNAseq) to compare how gene expression differs in people carrying APOE4 copies compared to those carrying APOE3 copies
.

Tsai said, "Using snRNAseq data obtained from postmortem human brains in a genotype-specific way, this paper shows very clearly that the effect of APOE4 on different brain cell types is very clear
.
" We observed convergence where lipid metabolism is disrupted, but when you really look further at the types of lipid pathways that are disrupted in different brain cell types, they're all different
.
I feel like lipid dysregulation may be a very fundamental biological property
behind many of the pathological phenomena we observe.
”

Many ways to study myelination

Postmortem brain samples came from the Religious Orders Study and the Rush Memory and Aging Project
.
The team's snRNAseq data contained more than 160,000 cells from 11 different types from the prefrontal cortex of 32 people--- 12 carrying two APOE3 copies, 12 carrying one APOE3 copy and one APOE4 copy, and 8 carrying two APOE4 copies
.
Postmortem human brain samples carrying APOE3/3 and carrying APOE3/4 are balanced in terms of diagnosis, sex, and age of Alzheimer's disease
.
All APOE4/4 carriers had Alzheimer's disease, and 5 out of 8 out of a total were female
.

Some results reflect known Alzheimer's pathology, but other patterns are new
.
One of the results showed that oligodendrocytes carrying APOE4 showed more expression of cholesterol-synthesizing genes and suffered disruption
of cholesterol transport.
The more copies of APOE4 people carry, the greater the impact
.
This is particularly interesting
given that a previous study by Tsai and Kellis' lab in 2019 (Nature, 2019, doi:10.
1038/s41586-019-1195-2) has shown a link between Alzheimer's disease and reduced expression of myelination genes in oligodendrocytes.

APOE4 and APOE-related lipid pathway changes
in Alzheimer's disease.
Image from Nature, 2022, doi:10.
1038/s41586-022-05439-w
.

By directly looking at postmortem human brain tissue using multiple techniques, these authors observed that in the APOE4-carrying brain, abnormal amounts of cholesterol accumulate within cells, particularly oligodendrocytes, but are relatively lacking
around nerve axons.

To understand why, the authors used patient-derived induced pluripotent stem cells to generate laboratory cell cultures genetically modified to carry oligodendrocytes of APOE4 or APOE3
.
Similarly, oligodendrocytes carrying APOE4 showed major lipid disruption
.
In particular, oligodendrocytes carrying APOE4 accumulate extra cholesterol within the cell, showing that the extra internal fat causes stress on organelles called the endoplasmic reticulum, which play a role in cholesterol transport, and does reduce cholesterol transport to their cell membranes
.
Subsequently, when co-cultured with neurons, oligodendrocytes carrying APOE4 failed to myelinate neurons in the same way as oligodendrocytes carrying APO3, regardless of whether the neurons carried APOE4 or APOE3
.

The authors also observed that APOE4 carriers had a lower
degree of myelination in the postmortem brain than APOE3 carriers.
For example, in the brain carrying APOE4, the myelin sheath around the axons that cross the corpus callosum (the structure that connects the cerebral hemispheres) is significantly thinner
.
The same is true of mice genetically modified to carry human APOE4 rather than mice that have been genetically modified to carry APOE3
.

Productive interventions

Eager to find a potential intervention, the authors focused on drugs that affect cholesterol, including statins that inhibit cholesterol synthesis and cyclodextrins
, which help with cholesterol transport.
Statins did not help, but applying cyclodextrin to APOE4-carrying oligodendrocytes cultured in Petri dishes reduced the accumulation of intracellular cholesterol and improved myelination
of neurons cultured with oligodendrocytes.
In addition, it also had these effects
in mice carrying APOE4.

Finally, the authors treated some APOE4-carrying mice with cyclodextrin and others with APOE4 did not, and had all APOE4-carrying mice undergo two different memory tests
.
APOE4-carrying mice treated with cyclodextrin performed significantly better in both tests, suggesting an association
between improved neuronal myelination and improved cognitive performance.

Tsai said the findings clearly suggest that interventions to correct specific lipid dysregulation in oligodendrocytes carrying APOE4 may help counteract APOE4's promoting effects on Alzheimer's disease
.

Tsai said, "Encouragingly, we observed a method
to rescue oligodendrocytes function and myelination in laboratory and mouse models.
But in addition to oligodendrocytes, we may also need to find clinically effective ways to process microglia, astrocytes, and blood vessels to really fight the disease
.
(Biovalley Bioon.
com)

Resources:

Joel W.
Blanchard et al.
 APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes, Nature, 2022, doi:10.
1038/s41586-022-05439-w.