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This article is the original of Translational Medicine Network, please indicate the source for reprinting
Written by Jevin
Apolipoprotein E gene (APOE) product Apolipoprotein E (APOE) plays a key role
in lipid metabolism, immunomodulation, and neurology.
It has three common subforms—APOE2, APOE3, and APOE4—that differ only in the positions of amino acids 112 and 158, but exhibit very different roles
in immune regulation.
On January 2, 2023, Shi Yigong's team at Westlake University published a research paper online in Cell Research (IF=46), which showed that LilrB3 is a putative cell surface receptor
for APOE4.
The study demonstrated that APOE4, rather than APOE2, interacts
specifically with leukocyte immunoglobulin-like receptor B3 (LilrB3).
Two discrete immunoglobulin-like domains of the LilrB3 extracellular domain (ECD) recognize positively charged surface plaques
on the N-terminal domain (NTD) of APOE4.
style="box-sizing: border-box;" _msthash="251139" _msttexthash="381004">Research background
01
Apolipoprotein E is one of the main lipid carriers responsible for transporting lipids to cells and tissues to regulate blood lipid levels
.
And the underlying mechanism of dependence on this APOE subtype remains a mystery
.
The immunomodulatory effects of APOE were first discovered as part of the inhibitory effect of plasma lipoproteins on T cell proliferation
.
APOE protein inhibits T cell proliferation and neutrophil activation, regulates macrophage function, promotes lipid antigen presentation, regulates inflammation and oxidation
.
For example, APOE4 in patients with multiple sclerosis (MS) accelerates the loss of brain tissue function, leading to early cognitive impairment
.
Research process
02
The APOE subtype also plays a clear role
in neurological and neurodegenerative diseases such as Alzheimer's disease (AD).
Compared with the most common APOE3 subtype, the APOE4 subtype has a relatively early age of onset, significantly increasing the risk of
AD.
In contrast, APOE2 is protective because it has a significantly lower risk
of AD compared to APOE3.
Early studies have shown that APOE plays a role
in β-amyloid deposition.
In addition to extensive studies of amyloid β clearance dependent on APOE subtypes, there is growing evidence that immune system dysfunction plays a key role
in AD pathology.
In a mouse model of Tau disease, knock-in of APOE4 resulted in significantly stronger activation
of microglia than APOE2.
Shi Yigong's research team determined that LilrB3 (leukocyte immunoglobulin-like receptor B3) is a candidate immune cell surface receptor for APOE4, not APOE2
.
In this study, the cryo-EM structure with an average resolution of 3.
0 Å of LilrB3-APOE4 binary complex was resolved, which provided a structural basis
for the specific identification of APOE4 by LilrB3.
Study results
03
The results of the study proved that APOE4 interacts
specifically with LilrB3 (leukocyte immunoglobulin-like receptor B3).
Two discontinuous immunoglobulin-like domains of the LilrB3 extracellular domain (ECD) recognize positively charged surface modules
on the N-terminal domain (NTD) of APOE4.
Consistent with further biochemical and structural analysis, APOE4, rather than APOE2, activates human microglia into a pro-inflammatory state
in a Lilrb3-dependent manner.
This study identified LilrB3 as a possible immune cell surface receptor for APOE4, which helps to understand the biological function and disease-related significance
of the apolipoprotein E subtypes.
Resources:
style="white-space: normal;box-sizing: border-box;">Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.
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