Abstract
Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD‐associated TREM2 variants to various forms of Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. High‐affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation. Pre‐incubation with Aβ is shown to block the interaction of APOE. In cellular assays, AD‐associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high‐affinity interaction between TREM2 and Aβ oligomers that can block interaction with another TREM2 ligand and ii) that AD‐associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization.
Highlights
The most prevalent form of dementia, Alzheimer’s disease (AD), is hypothesized to be triggered by accumulation of aggregated amyloid-b (Ab) followed by a “cascade-like” chain of events that includes induction of tauopathy, neurodegeneration, and alterations in innate immune signaling (Hardy & Selkoe, 2002; Musiek & Holtzman, 2015)
These were spun at 18,000 g to pellet fibrillar Ab42 (fAb) associated proteins. sTREM2, sTREM2-R47H and sTREM2-R62H were enriched in the fAb pellet (Figs 1A and EV1A), whereas the Fc control was not detected in the pellet
Triggering receptor expressed on myeloid cells 2 (TREM2) appears capable of mediating Ab internalization and Ab oligomers induce Nuclear factor of activated T-cell (NFAT) singling through TREM2
Summary
The most prevalent form of dementia, Alzheimer’s disease (AD), is hypothesized to be triggered by accumulation of aggregated amyloid-b (Ab) followed by a “cascade-like” chain of events that includes induction of tauopathy, neurodegeneration, and alterations in innate immune signaling (Hardy & Selkoe, 2002; Musiek & Holtzman, 2015). Even more compelling are data showing that coding variants in three different genes (TREM2, PLCG2, and ABI3), whose transcripts are expressed primarily in microglial cells in the brain, alter risk for AD (Golde et al, 2013; Jin et al, 2014; Sims et al, 2017). Despite these associations between the immune system and AD, there is little consensus as to how alterations in the immune system mechanistically alter AD risk. Further understanding of how genetic risk factors impact the immune function will be important to guide therapeutic development, that to date has largely focused on anti-inflammatory strategies (Chakrabarty et al, 2015)
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