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Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation.

ABSTRACT: TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial.We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes.We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells.Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.

SUBMITTER: Song W

PROVIDER: S-EPMC5299056 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation.

Song Wilbur W Hooli Basavaraj B Mullin Kristina K Jin Sheng Chih SC Cella Marina M Ulland Tyler K TK Wang Yaming Y Tanzi Rudolph E RE Colonna Marco M

Alzheimer's & dementia : the journal of the Alzheimer's Association 20160809 4

<h4>Introduction</h4>TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial.<h4>Methods</h4>We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes.<h4>Results</h4>W ...[more]

PMID: 27520774

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Project description:Single nucleotide variations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) have been linked to both late-onset Alzheimer's disease and behavioral variant frontotemporal dementia (FTD), the latter presenting either in isolation or with cystic bone lesions in a condition called Nasu-Hakola disease. Models of the extracellular domain of TREM2 show that Nasu-Hakola disease-associated mutations are grossly inactivating by truncation, frameshift, or unfolding, that Alzheimer's disease (AD)-associated variants localize to a putative ligand-interacting region (PLIR) on the extracellular surface, and that FTD-associated variants are found in the hydrophobic core. However, while these disease-associated residues are predicted to play some role in disrupting ligand binding to the extracellular domain of TREM2, how they ultimately lead to disease remains unknown. Here, we used in silico molecular modeling to investigate all-atom models of TREM2 and characterize the effects on conformation and dynamical motion of AD-associated R47H and R62H as well as FTD-associated T96K, D86V, and T66M variants compared to the benign N68K variant and the common variant. Our model, which is based on a published 2.2 Å resolution crystal structure of the TREM2 extracellular domain, finds that both AD- and FTD-associated variants cause localized instability in three loops adjacent to the PLIR that correspond to the complementarity-determining regions (CDRs) of antibodies. This instability ultimately disrupts tethering between these CDRs and the core of the immunoglobulin domain, exposing a group of otherwise-buried, negatively charged residues. This instability and exposure of negatively charged residues is most severe following introduction of the T66M variant that has been described as causing FTD even in the heterozygous state and is less severe following introduction of variants that are less strongly tied to FTD or of those associated with AD. Thus, our results provide further evidence that the proposed loss-of-function caused by neurodegenerative disease-associated variants may be driven by altered conformational stability of the ligand-interacting CDR and, ultimately, loss of affinity or specificity for TREM2 ligands.

Dataset Information

Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation.

Publications

Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation.

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