The Alzheimer's disease risk variant APOE4 is associated with impaired myelin assembly

No single gene variant is more likely to cause Alzheimer's disease
than APOE4.
But exactly how this gene stimulates brain damage has been a mystery
.
A study published today in Nature suggests that APOE4 variants are associated with defects in cholesterol processing in the brain, which in turn lead to defects
in the insulating sheaths that surround nerve fibers and promote their electrical activity.
Preliminary results suggest that these changes may contribute to memory and learning disabilities
.
This study suggests that drugs that restore cholesterol processing in the brain could treat the disease
.
The results of the clinical trial of Roche Pharma's monoclonal antibody drug for amyloid protein recently announced did not meet expectations, which made the research of Alzheimer's disease treatment drugs more confusing
.

cholesterol

Inheriting one APOE4 gene variant increases the risk of Alzheimer's disease by about 3 times; With two copies, the odds increase by 8 to 12 times
.
In the brain, the interaction between the protein encoded by APOE4 and amyloid, a substance involved in brain cell death, partly explains this connection
.
But these interactions aren't the whole
story.

As neuroscientist Li-Huei Tsai and her colleagues at the Massachusetts Institute of Technology (MIT) in Cambridge report today in the journal Nature, APOE4 prompts the central nervous system cells that produce myelin insulators — oligodendrocytes — to falsely accumulate cholesterol inside cells, interfering with the normal function of oligodendrocytes—their ability to
coat nerve fibers with a lipid-rich myelin protective membrane.
Electrical signals in the brain slow down and cognitive abilities are usually affected
.

Oligodendrocytes are the cells of the central nervous system that produce myelin, a lipid-rich, multilayer membrane that envelops nerve cells in a cable-like extension for effective insulation, rapid impulse conduction, and metabolic support
.
In diseases such as multiple sclerosis, a temporary or permanent loss of myelin translates into a flare-up
of the disease.
But the changes observed in oligodendrocytes and their precursor cells in multiple sclerosis and Alzheimer's disease suggest that these cells may also directly contribute to the onset or progression
of the disease.

Cai's team has previously linked lipid changes to dysfunction in other types of cells, including some that provide structural support for neurons, and some that
provide immune protection to the brain.
The latest findings add oligodendrocytes and their essential myelin function to reveal the previously unknown role of oligodendrocytes in Alzheimer's disease, involving changes in
lipid carrier protein apolipoprotein E (APOE) and cholesterol metabolism.
Julia TCW, a neuroscientist at Boston University in Massachusetts, commented, "It's really putting all the pieces together
.
"

Research highlights

Choi and her colleagues collaborated with MIT computational biologist Manolis Kellis to analyze gene activity patterns in prefrontal cortex (the cognitive center of the brain) tissue in 32 deceased people with a history of Alzheimer's disease who carried two, one, or no APOE4 copies
.
When the researchers examined brain cells affected by APOE4, they noticed abnormalities in many lipid metabolic systems, and defects in the way oligodendrocytes handled cholesterol appeared to be "particularly severe.
"

The team cultured human oligodendrocytes
with different forms of the APOE gene.
The team found that cells with APOE4 variants tended to store cholesterol inside
organelles.
They excrete relatively little cholesterol, which makes them less good at forming myelin.

The researchers then used cyclodextrin to stimulate cholesterol clearance and treat
the cells carrying APOE4.
This helps restore the formation
of myelin.
The researchers also found that in mice carrying two copies of the APOE4 gene, cyclodextrin appeared to flush cholesterol out of the brain, improving cholesterol flow into the myelin sheath, and boosting the animals' cognitive abilities
.

The nemesis of cholesterol

The results in mice dovetailed with the experience of an Alzheimer's patient who took a similar cyclodextrin formulation under a special drug access program, and the drug's manufacturer, Cyclo Therapeutics of Gainesville, Florida, reported in 2020 that the patient's cognitive function remained stable
over 18 months of treatment.

Gregory Thatcher, a chemical biologist at the University of Arizona, commented, "This is consistent with the statement that cholesterol needs to be in the
right place.
" However, cyclodextrin may not be an ideal way
to correct lipid imbalances in the brain.
Study co-author neuroscientist Leyla Akay said
.
"It just consumes cholesterol
from the cells.
"

But Tsai and her team have helped bring cholesterol dysregulation into Alzheimer's research, so better treatments
may emerge.
"This study highlights the importance of cholesterol in the brain," says Irina Pikuleva, a biochemist at Case Western Reserve University in Ohio.

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