Alzheimer's disease is still related to the liver?

▎Editor of WuXi AppTec's content team Alzheimer's disease is a neurodegenerative disease that affects brain function
.

After years of research, beta amyloid (Aβ) is considered to be a key protein that promotes the development of Alzheimer's disease
.

Plaques formed by the accumulation of this protein in the brain can cause the degeneration and death of nerve cells.
It is a landmark in patients with Alzheimer's disease or in various animal models used to study neurodegenerative diseases.
Pathological characteristics
.

Recently, a new study showed that amyloid produced by the liver may also enter the brain and cause neurodegeneration
.

This finding suggests that the liver may play an important role in the occurrence or development of Alzheimer's disease
.

▲This study was published in the open-access journal PLOS Biology.
Although the performance of Aβ in the brain attracts attention, it cannot be ignored that Aβ also exists in some peripheral organs
.

In the blood, more than 90% of Aβ binds to apolipoprotein in the form of a complex
.

Some previous evidence suggests that the blood level of Aβ is related to the amyloid load in the brain and cognitive decline
.

However, it has always been a huge challenge to verify whether the Aβ produced in the periphery has the possibility of causing disease, because it is difficult to distinguish the Aβ protein from the peripheral and the brain
.

In order to overcome this challenge, scientists from Curtin University in Australia have used genetic modification to establish a mouse strain so that the pathogenic variant of the human amyloid precursor gene (APP695) is only found in the liver cells of mice.
Medium specific expression (referred to as HSHA strain, namely hepatocyte-specific human amyloid)
.

Therefore, Aβ synthesized in the liver of mice can be distinguished from Aβ produced in the brain and other parts
.

The researchers observed through the tracer that the Aβ produced in the liver of HSHA mice was carried by lipoproteins rich in triglycerides and entered the brain from the periphery through the blood
.

As we age, Aβ signals in the cerebral cortex, hippocampus and thalamus increase
.

In the brain tissues of HSHA mice aged 6 to 12 months, human Aβ increased significantly
.

At the same time, they found that the brains of these mice showed obvious neurodegeneration and brain atrophy, accompanied by brain capillary dysfunction and vascular inflammation, which are common symptoms in Alzheimer's disease
.

▲In the hippocampus tissue of HSHA mice, there are obvious active astrocytes (white) and oxidative stress (green) around the capillaries (magenta) (picture source: reference [2]; Credit: John Charles Louis Mamo, Lam V et al.
, 2021, PLOS Biology) Researchers also examined the cognitive abilities of mice through behavioral tests.
They also showed that the performance of HSHA mice was lower when completing learning tasks that depend on hippocampal function.
Normal mice of the same age
.

Based on the results of these experiments, Aβ produced in the periphery has the ability to cause neurodegeneration, and Aβ produced in the liver may be a potential factor leading to human diseases
.

Image source: 123RF researchers pointed out that if Aβ produced by the liver is a significant pathogenic factor, these findings will have great significance for understanding Alzheimer's disease
.

Because so far, many disease models focus on the excessive production of Aβ in the brain, but this simulates a small number of genetic cases; on the contrary, for most cases of Alzheimer's disease, the excessive production of Aβ in the brain is not considered to be the core of the cause.
And life>
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It is worth noting that a high-fat diet may accelerate the liver's production of Aβ
.

Dr.
John Mamo, who led the study, added that the effect of peripheral Aβ on brain capillaries may be critical in the course of the disease: "Although in-depth research is needed, this finding suggests that lipoprotein starch can be specifically targeted through diet and some Protein-like drugs may be able to solve a large number of toxic protein deposits in the blood, which is expected to reduce the risk of disease or slow the progression of Alzheimer’s disease
.

"Reference: [1] Lam V, Takechi R, Hackett MJ, Francis R, Bynevelt M, Celliers LM, et al.
(2021) Synthesis of human amyloid restricted to liver results in an Alzheimer disease--like neurodegenerative phenotype.
PLoS Biol 19(9): e3001358.
https://doi.
org/10.
1371/ journal.
pbio.
3001358[2] Protein from the liver may cause Alzheimer's disease in the brain.
Retrieved Sep.
15, 2021 from https://