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Published on: December 26, 2016
TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model
Yaming Wang1, Marina Cella2, Kaitlin Mallinson3
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Abstract:
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency worsens Alzheimer's disease pathology by impairing microglial response to amyloid plaques. The R47H mutation disrupts TREM2's lipid sensing, highlighting its role in neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor implicated in Alzheimer's disease (AD) risk.
- A rare R47H TREM2 mutation significantly increases AD susceptibility.
Purpose of the Study:
- To investigate the functional consequences of TREM2 deficiency and the R47H mutation in an AD mouse model.
- To elucidate the molecular mechanisms underlying TREM2's role in microglial response to amyloid pathology.
Main Methods:
- Utilized the 5XFAD mouse model of AD to study TREM2 deficiency and haploinsufficiency.
- Assessed microglial clustering, apoptosis, and response to amyloid-beta (Aβ) plaques.
- Investigated TREM2's interaction with lipid ligands associated with Aβ and neuronal damage.
Main Results:
- TREM2 deficiency and haploinsufficiency exacerbate Aβ accumulation.
- Microglia in TREM2-deficient mice fail to cluster around plaques and exhibit increased apoptosis.
- TREM2 senses anionic and zwitterionic lipids on damaged neurons and associated with Aβ.
- The R47H mutation impairs TREM2's ability to detect these critical lipid ligands.
Conclusions:
- TREM2 is crucial for effective microglial response to Aβ pathology in AD.
- Impaired lipid sensing by TREM2, particularly the R47H variant, contributes to AD pathogenesis.
- TREM2 acts as a sensor for damage-associated lipid patterns, mediating microglial neuroprotective functions.
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