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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.
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
.
APOE4 is the strongest genetic risk factor for Alzheimer's disease, and the study found that LilrB3 is an APOE4-specific immune cell surface receptor
.
Since LilrB3 is abundantly expressed in lymphocytes, it may play a role in cellular clearance of β-amyloid (Aβ).
Interferon-stimulating gene (ISG) activation triggered by LilrB3-APOE4 interactions may ultimately hinder phagocytic function of microglia and promote Aβ deposition, thereby increasing the risk
of Alzheimer's disease (AD).
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
.
In addition, different subtypes of APOE also play an important role in neurological and neurodegenerative diseases such as Alzheimer's disease (AD).
For example, APOE4 can significantly increase the risk of Alzheimer's disease and 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.
APOE2, on the other hand, significantly reduces the risk of
Alzheimer's disease.
Previous studies have shown that APOE plays a role in β-amyloid (Aβ) deposition, in addition, much research evidence shows that immune system dysfunction plays a key role
in Alzheimer's disease pathology.
In particular, abnormal activation of microglia, leading to neurotoxic cytokine release and synaptic pruning, has been linked to
memory loss and the development of Alzheimer's disease.
In a mouse model of Tau proteinopathy, knocking in the APOE4 gene resulted in significantly stronger activation
of microglia compared to APOE2.
In this study, the 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.
Two discontinuous immunoglobulin-like domains of the LilrB3 extracellular domain (ECD) recognize positively charged surface modules
on the N-terminal domain (NTD) of APOE4.
Further atomic structure elucidation revealed how the two APOE4 molecules specifically bind to the two LilrB3 molecules, bringing their intracellular signaling motifs close by
forming heterotetrameric complexes.
Consistent with further biochemical and structural analysis, APOE4, rather than APOE2, activates human microglia into a pro-inflammatory state
in a Lilrb3-dependent manner.
Overall, this study identified LilrB3 as an immune cell surface receptor for APOE4, which helps to understand the biological function and disease-related significance
of the various isoforms of apolipoprotein E.
LilrB3 identifies the structural basis of APOE4
This is also the first time that APOE-binding receptor complexes have been structurally elucidated, revealing clues
about APOE isotype specificity and receptor-mediated signaling.
Link to the paper: style="letter-spacing: normal;color: rgb(136, 136, 136);font-size: 12px;" _mstmutation="1" _istranslated="1">
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