Nature: Cai's team reveals how the Alzheimer's disease gene APOE4 damages the brain and finds potential therapies

Written by Nagashi

EditorWang Duoyu

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Alzheimer's disease (AD), commonly known as "Alzheimer's disease", is a type of central nervous system degenerative disease
that mainly occurs in the elderly and is characterized by progressive cognitive dysfunction and behavioral damage.
As the average human life expectancy increases, so does the prevalence of Alzheimer's disease
.

According to data released by the China Association for the Ageing, there are about 15.
07 million Alzheimer's disease patients among the elderly aged 60 and above in China, causing a huge burden
to families and society.
Unfortunately, despite the much effort that the scientific community has invested in Alzheimer's disease, there is still no very effective treatment plan to prevent or cure Alzheimer's disease
.

On November 16, 2022, the team of Lihui Cai of the Massachusetts Institute of Technology (MIT) published a report on Nature entitled: APOE4 Research paper on impairs myelination via cholesterol dysregulation in oligodendrocytes.

The study constructed a single-cell map of the transcriptional role of APOE4, the strongest genetic risk factor for Alzheimer's disease, in the aging human brain, and established a functional link between APOE4, cholesterol, myelination and memory, providing opportunities for the treatment of Alzheimer's disease
.

Professor Cai Lihui, a corresponding author of the paper and a neuroscientist at MIT, said that the paper clearly shows that APOE4 has a very obvious effect
on different brain cell types in a genotype-specific way through single-cell sequencing of postmortem human brains.
Encouragingly, this study has observed ways to salvage oligodendrocytes function and myelination in mouse models
.

Genetic variation is the most important risk factor for Alzheimer's disease, and genome-wide association analysis studies have shown that APOE4 is the strongest genetic risk factor for Alzheimer's disease, and APOE4
is present in 40%-50% of Alzheimer's disease patients.
The risk of Alzheimer's disease increases 3-fold when there is one copy of APOE4 and 8-12-fold
when both copies are APOE4.

Several studies have found that APOE4 is associated with
increased β-amyloid deposition, excessive phosphorylation and aggregation of tau protein, and accelerated cognitive decline.
However, the mechanism by which APOE4 mediates these effects is not fully understood
.
Therefore, elucidating the molecular mechanism and cellular pathway of APOE4-induced Alzheimer's disease is important
for the prevention and cure of Alzheimer's disease.

APOE is a lipid and cholesterol transporter, and APOE4 is one of the allele forms that alters the accessibility of lipid-binding regions, thereby interfering with cholesterol and lipid transport
.
To gain a more comprehensive understanding of the effects of APOE4 on the human brain, the research team first performed single-cell nuclear transcriptome sequencing (snRNA-seq) on the prefrontal cortex (the cognitive center of the brain)
tissue of 32 deceased patients.