PNAS blockbuster: Cholesterol affects Alzheimer's disease plaque deposition treatment of new opportunities will be born

Alzheimer’s disease (AD) is a common type of Alzheimer’s disease.
The main pathological features include plaques formed by β-amyloid protein deposition, neurofibrillary tangles formed by hyperphosphorylation of tau protein, inflammation, and Decrease in touch and loss of neurons
.

Previous in vitro experiments have shown that the production of amyloid β is related to apolipoprotein e in astrocytes, but the endogenous regulation process of its production is currently unclear

In order to clarify the regulation process of β-amyloid protein in vivo, a study led by scientists from the Scripps Research Institute in the United States carried out related research using advanced microscopy technology of super-resolution imaging and found that β-amyloid protein is involved in neurons.
Accumulation is tightly regulated by cholesterol synthesis and the transport of apolipoprotein e from astrocytes
.

Related research results were published on PNAS under the title Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

https://doi.
org/10.
1073/pnas.
2102191118

Regarding Alzheimer's disease, a complete cure has not yet been found.
From the relevant research, cholesterol is likely to play an important role in the pathogenesis of AD
.

Therefore, clarifying how cholesterol plays a role in the pathogenesis of Alzheimer's disease is likely to make it a new therapeutic target for AD

Apolipoprotein e of astrocytes is necessary for the transport of cholesterol from astrocytes to neurons.
Other cholesterol transport proteins in the brain may also be responsible for the transport of cholesterol, but apolipoprotein e transports cholesterol to neurons.
The main protein
.

Astrocytes produce cholesterol and transport it to neurons through apolipoprotein e.

On the one hand, apolipoprotein e transports amyloid precursor protein (APP) in and out of liposomes by means of cholesterol derived from astrocytes.
APP interacts with β and γ secretases to produce β amyloid, which then aggregates to form β Amyloid plaques
.

On the other hand, APP interacts with the third enzyme α secretase to produce soluble APP fragment sAPP-α, which in turn reduces the production of β amyloid

The production mechanism of beta amyloid

The cholesterol content in the brain of AD patients is high.
Researchers predict that the attenuation of cholesterol in astrocytes will reduce the concentration of beta amyloid formed in the body
.

In order to test this hypothesis, they established a "3xTg-AD" mouse model.

These experimental data prove that the targeted deletion of cholesterol synthesis in astrocytes significantly reduces the deposition of β-amyloid and tau protein phosphorylation in the AD mouse model
.

Studies have shown that when the cholesterol content is low, apolipoprotein e promotes the action of the precursor protein APP and α secretase, and produces more sAPP-α; when the cholesterol content is high, apolipoprotein e will reduce the precursor protein APP It is transferred to β and γ secretase to produce β amyloid

The lack of cholesterol synthesis in astrocytes prevents the production of beta amyloid and tau phosphorylation in the body

Researchers’ experiments proved that astrocytes are the key regulators of β-amyloid accumulation.
The increase in cholesterol promotes the reaction of APP with β- and γ-secretase in lipid clusters to accelerate the accumulation of β-amyloid, and β-amyloid The accumulation of β-amyloid protein further accelerates the deposition of β-amyloid plaques
.

This study provides a molecular background for understanding the regulation of cholesterol on amyloid β and its correlation with Alzheimer’s disease (AD).
It not only contributes to the understanding of Alzheimer’s disease, but also serves as a role for cholesterol-related genes.
The role of its risk factors provides an explanation
.

Revealing the regulation mechanism of cholesterol on β-amyloid protein may bring new opportunities for the prevention and treatment of Alzheimer's disease!