TREM2 lipid sensing sustains microglia response in an Alzheimer’s disease model

By Yaming Wang, M. Cella, Kaitlin Mallinson, Jason D. Ulrich, Katherine L. Young, M. Robinette, Susan Gifillian, G. M. Krishnan, S. Sudhakar, Bernd H Zinselmeyer and 3 more. Cell, 2015

1,505 citations recorded by the source corpus.

Summary Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia 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 dysfunctional response of microglia, which become apoptotic and fail to cluster around Aβ plaques. 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 microglia response to Aβ accumulation.

Subfields: Complementary and alternative medicine, Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/1352f7f24299fb3f6a383e202ab7a05a40e30326

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In Immunology

1. D. Holtzman
2. Chao Gao
3. Shengdi Chen
4. Yuyan Tan
5. Jingwen Jiang
6. O. Butovsky
7. M. Colonna
8. B. Barres

In Neurology

1. D. Holtzman
2. O. Butovsky
3. Chao Gao
4. Shengdi Chen
5. Yuyan Tan
6. Jingwen Jiang
7. M. Colonna
8. B. Barres

Citations in the corpus

• Role of neuroinflammation in neurodegeneration development (2023, background): “However, other studies found that R47H variant affected TREM2 function by altering its binding ability rather than expression.(192,197,198) R47H mutation also leads to multiple changed in AD pathology.”
• Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, methodology): “Downloaded from https://academic.oup.com/brain/article-abstract/139/4/1265/2464332 by guest on 27 July 2018”
• TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques (2016, methodology): “…response to Aβ deposits in all AD models, changes in Aβ burden develop more slowly; therefore, the discrepancies in Aβ accumulation may be a result of the varied timing of the analyses—8 mo in 5XFAD mice (Wang et al., 2015) and 3–4 mo in APP PS1-21 mice (Ulrich et al., 2014; Jay et al., 2015).”
• Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation (2016, background): “Since the recent study indicates that TREM2 loss-of-function and TREM2-R47H variant attenuate lipid-sensing ability in microglia to mount a sustained response to neuronal injury in mouse AD models (Wang et al., 2015), these results raise the possibility that the elevated level of TREM2 in Grn!”