"Nature" blockbuster: MIT cow Cai Lihui's team found for the first time that ApoE4 causes cholesterol to be deposited inside oligodendrocytes, intervening in cholesterol or becoming a new treatment for Alzheimer's disease

*For medical professionals only

Excited heart, trembling hands, my idol Teacher Cai, sent "Nature" again!

A few days ago, two phase 3 clinical trials of gantenerumab announced that they did not reach the clinical endpoint, which really made the singularity cake a little sad, the "failure curse" of the Alzheimer's disease (AD) sinkhole is too long-lasting, in recent years, it is almost to watch a little hope emerge from various new drugs, and then fail, fail and fight again.
.
.
Among them, the γ frequency neuromodulation therapy developed by Cai Lihui's team is quite valuable, the technology is simple and convenient, the journey has been smooth, and the clinical data released last year is also very eye-catching
.

While waiting for this technology to go on the market, on the other hand, we can also see what new discoveries
Teacher Cai has.
The paper, published today in Nature, has discovered a new mechanism
for the greatest risk gene for AD, ApoE4.
Cai's team and the team of Manolis Kellis, another computational biologist at MIT, analyzed the gene expression of autopsy brain samples from 32 volunteers and found that ApoE4 leads to the wrong accumulation of cholesterol in oligodendrocytes, which in turn affects the function of
neuronal myelin sheath.

Amazingly, regulating cholesterol transport through drugs can solve this problem well and significantly improve the cognitive function of mice carrying the ApoE4 gene! This must point out a new way for the treatment of AD
.

"Nature" is very face-saving with two reviews and a podcast, the podcast has been cut for everyone and placed at the top, interested readers can listen to it
.

ApoE4 can be said to be an old friend of everyone who follows AD
.
ApoE4 is the most important genetic risk factor for AD, although it is only one amino acid different from ApoE3, but carrying an ApoE4 allele can increase the risk of AD by 3-4 times, and if it is two ApoE4 alleles, the risk will rise to 8-12 times
.

But how exactly does ApoE4 affect the progress of AD? Considering that 40%-50% of AD patients carry ApoE4, if this process can be understood and effective targets can be found, then it means that half of the patients have hope to use drugs
.

The researchers thought of a trick this time - isn't it just finding a needle in a haystack, sieve!

The good thing is that I exaggerated
.
The researchers obtained autopsy brain samples from 32 volunteers, including 12 ApoE3/3, 12 ApoE3/4, and 8 ApoE4/4, and performed mononuclear RNA sequencing (snRNA-seq) on their prefrontal cortex (PFC) cells, ready to see if ApoE4 had any effect
on gene expression.
Among the volunteers carrying ApoE3, AD and gender were considered and in place
.

Red lipids can be seen clustered around the nucleus

Excluding the unqualified, the researchers finally obtained a total of 164741 mononuclear transcriptome data, and after analysis, they found 486 molecular processes affected by ApoE4, including various inflammation, immunity, synapses, energy metabolism-related pathways, in short, and some of the previously discovered phenomena
.

Don't forget, APOE is called apolipoprotein, and its job is to process and transport lipids, so the researchers focused the next analysis on lipid-related pathways
.
This analysis is not important, and interesting results have emerged, the researchers found that in the brains of ApoE4 carriers, lipid accumulation and lipid types increased, and it is worth noting that the location of cholesterol storage changed
greatly.

In ApoE3/3 nerve cells, cholesterol is mainly present near neurofilament, which can be understood as near axons; But in nerve cells carrying ApoE4, the proportion plummeted from 58% to 19%, cholesterol was more likely to be present in the cell, and more than 80% were located in the
endoplasmic reticulum.

In nerve cells carrying ApoE4, cholesterol is transferred from the nerve filaments to the cell body

What's more interesting is that this change in cholesterol is mainly found in an inconspicuous nerve cell, oligodendrocytes
.

Oligodendrocytes are cells in the central nervous system that produce myelin, and the myelin sheath wraps the axons of neurons, acts as insulation, and also participates in the metabolism
of neurons.
Cholesterol is an important material
for the formation and maintenance of myelin sheath.

Sure enough, under the influence of ApoE4, oligodendrocytes with cholesterol do not seem to do this job, and ApoE4 carriers have fewer and thinner neuronal axonal external myelin sheaths.

The external myelin sheath of the ApoE4/4 axons is thinner and the axon-to-myelin-containing total diameter ratio is higher

Now that the pot falls to cholesterol, can inhibiting cholesterol biosynthesis or promoting cholesterol transport improve the problem?

Here the researchers tried three drugs, including two small molecules that inhibit cholesterol synthesis, simvastatin and atorvastatin, and a small molecule that promotes cholesterol transport, 2-hydroxypropyl-β-cyclodextrin
.

There is a saying that this cyclodextrin is a bit of a source
.
The year before last, a pharmaceutical company called CycloTherapeutics reported data that a patient with late-onset AD was treated with a cyclodextrin candidate drug for Niemann-Pick disease type C (commonly known as childhood AD), and after 18 months of treatment, neurological symptoms and cognitive levels remained stable, and speech, mood and behavior improved
.

The effect of cyclodextrin is also quite good, which can significantly improve the distribution
of cholesterol in ApoE4/4 neurons.
Even more exciting is the significant improvement in learning and memory in ApoE4/4 mice
.

Cyclodextrin significantly improves the problem of cholesterol "ballast"

The learning ability of mice was significantly improved after cyclodextrin treatment

From this we see a new path, aiming for cholesterol! This is not only cyclodextrin, in addition to drugs, diet and lifestyle can also play a certain intervention effect, depending on how the specific plan is designed
.
In fact, the relationship between lipids and various nerve cells, Mr.
Cai's team has also had a lot of research before, recently we wrote an article with microglia, posted on another matrix number singularity thought, this number focuses on the field of neuropsychiatry, I recommend you pay attention to it
.

Another AD-related paper published this week in Nature is also interesting, finding that the most common amyloid Medin is actually a "symbiotic" state with Aβ precipitation, which may also be an effective target
.
This paper is still OA, it just feels very profitable, Amway!

Editor's nagging

Mr.
Cai, what about your Phase 3 clinical trial!

Resources:

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The author of this article Dai Siyu