Dangerous genes that make Thor breathe

Just last week, Chris Hamsworth, also known as "Thor," suddenly announced a temporary retirement
.
He himself said this was because he recently underwent a medical examination while working on a documentary about health and was found to carry APOE4, a notorious "genetic risk factor" for Alzheimer's disease.

There are three allele variants of APOE (apolipoprotein E), namely APOE2, APOE3, and APOE4
.
APOE4 is considered a risk factor for Alzheimer's disease (but it is not a disease-causing gene itself).

Carrying one copy of the APOE4 variant triples a person's risk of developing Alzheimer's disease and about 10-fold
with two copies.

"Thor" unfortunately inherited two copies of APOE4 from both parents, and his grandfather was also a patient
with Alzheimer's disease.
This made Hamsworth rethink the meaning of life and family, and take a break from work
.

At present, scientists believe that APOE4 increases the amyloid load
β the human brain.
But the fundamental reason behind this, and how to help patients with medical means, is still unknown
.

Recently, a team of researchers brought some new insights
about APOE4.
They believe that in people carrying APOE4 risk variants, a class of key brain cells can "mismanage" important lipid cholesterol, another sign that APOE4 brings disease by destroying lipids in the brain.

The paper has been published in
Nature.

Inspection by a variety of means

The new study combines evidence
from postmortem human brains, laboratory human brain cell cultures, and mouse models of Alzheimer's disease.

The results of the snRNAseq (single-cell nuclear RNA sequencing) study of the postmortem brain included 11 different types of cells from the prefrontal cortex of 32 people, totaling more than 160,000 cell individuals
.
Of these, 12 carried two copies of APOE3 (APOE3/3), 12 copies of APOE3 and APOE4 (APOE3/4), and 8 copies of APOE4 (APOE4/4).

The APOE3/3 and APOE3/4 samples were balanced in terms of diagnosis, sex, and age of Alzheimer's disease
.
All APOE4/4 carriers have Alzheimer's disease and 5 of these 8 are female
.

Postmortem brain tissue with obvious staining marks of myelin sheath (first row).

Myelination was less pronounced
in people with one copy of APOE4 (second row).
(Photo: The Picower Institute)

Some results reflect known pathological features of Alzheimer's disease, but there are other patterns that are new
.

They found that when people carried one or two copies of APOE4 (as opposed to the more common, risk-neutral version of APOE3), oligodendrocytes carrying APOE4 introduced more expression of cholesterol-synthesis genes and disruption of cholesterol trafficking, making it impossible to transport lipid molecules to wrap the long vine-like axon "line.
" Establish connections
to brain pathways.

The absence of this protective "insulating layer" of fat, called myelin, can be an important factor
in the pathology and symptoms that contribute to Alzheimer's disease.
Because without proper myelin, communication between neurons degenerates
.
The more copies of APOE4 people carry, the greater the impact
.

The team looked directly at the tissue with the help of various techniques and found that in APOE4's brain, abnormal amounts of cholesterol accumulate in the cells, especially oligodendrocytes, but are relatively lacking
around the axons.

To understand the reasons behind this phenomenon, the team used patient-derived induced pluripotent stem cells to create laboratory cell cultures of oligodendrocytes that differ
only in the APOE4 or APOE3 variants.

Similarly, APOE4 cells exhibited major lipid disruption
.
In particular, affected oligodendrocytes hoard extra cholesterol
inside.
The extra internal fat puts pressure on an organelle in the cell called the endoplasmic reticulum, which plays a role in cholesterol transport, and it does reduce cholesterol transport
outside the membrane.

Subsequently, when they were co-cultured with neurons, APOE4 oligodendrocytes failed to myellate neurons in the same way as APOE3 cells, regardless of whether the neurons carried APOE4 or APOE3
.

The team also observed that APOE4 carriers had lower levels of myelination in the postmortem brain than APOE3 carriers
.
For example, in the APOE4 brain, the sheath around the axon that passes through the corpus callosum (the structure that connects the cerebral hemispheres) is significantly thinner
.
The same is true for
mouse models designed to carry human APOE4 and APOE3.

A productive intervention

A series of recent studies have told us that APOE4 disrupts the unique way
key brain cell types, including neurons, astrocytes, and microglia, process lipids.

The team wanted to find a potential intervention
.
They focused on a number of drugs that affect cholesterol, including statins (which inhibit synthesis) and cyclodextrin, which can help with cholesterol transport
.

The results showed that statins had no effect, but applying cyclodextrin to APOE4 oligodendrocytes cultured in a petri dish reduced the accumulation of cholesterol within the cells and improved the myelin sheath
co-cultured with neurons.
In addition, it also showed these effects
in the APOE4 mouse model.

Finally, the team had some APOE4 mice treated with cyclodextrin and others not, and had them all undergo two different memory tests
.
Mice treated with cyclodextrin performed significantly better in both tests, suggesting an association between improved myelin sheath and improved cognitive performance.

Scientists believe that a clear picture is unfolding before us, and that interventions to correct certain cell-specific lipid dysregulation may help counteract the effects
of APOE4 on Alzheimer's disease.

But in addition to oligodendrocytes, clinically effective ways to deal with other kinds of cells, such as microglia, astrocytes, and blood vessels, need to be found before we have a chance to truly fight the disease
.

#Creative Team:

Compiled by Måka

Typesetting: Wenwen

#Reference source:

https://picower.
mit.
edu/news/alzheimers-risk-gene-undermines-insulation-brains-wiring

#Image source:

National Institute on Aging, NIH, Flickr, CC BY-ND