Over the past few years, a growing number of TREM2 (triggering receptor expressed on myeloid cells 2) gene polymorphisms have been linked to an increased risk of Alzheimer disease (AD), but whether these variants cause loss or gain of TREM-2 protein function has remained unclear. New research published in Alzheimer's & Dementia sheds light on this issue by providing evidence that both deficiency and hyperactivity of TREM-2 can contribute to AD risk.
“In our previous studies, we discovered that the R47H risk allele of TREM2 showed greatly reduced TREM-2 activation in vitro compared with the common variant, suggesting a loss of function,” explains senior author Marco Colonna. “With the identification of a plethora of other rare TREM2 variants, we wanted to see if diminished TREM-2 function was a conserved feature.”
Colonna and colleagues developed an in vitro cell-based reporter assay, in which downstream calcium signalling provided a measurable readout of TREM-2 activation. The assay was performed in a series of reporter cell lines, each of which had been engineered to express a different AD-associated variant of TREM2.
simply boosting TREM-2 activity may not lead to a beneficial effect
The researchers found that most of the risk variants, including the aforementioned R47H, were associated with reduced TREM-2 signalling, but two variants seemed to have the opposite effect. “Surprisingly, we discovered that two rare variants, D87N and T96K, actually enhanced TREM-2 activation,” reports Colonna. “Our results suggest that simply boosting TREM-2 activity may not lead to a beneficial effect, and that TREM-2-targeted therapeutics may have to be carefully tuned to achieve the optimal response.”
Colonna's team also discovered that HDL and LDL are ligands for TREM-2, and that AD-associated polymorphisms influence the ability of the receptor to engage with these lipoproteins. “Given the importance of HDL in neurodegenerative diseases, this observation opens up interesting new avenues of investigation,” comments Colonna.
References
Song, W. et al. Alzhiemer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. http://dx.doi.org/10.1016/j.jalz.2016.07.004 (2016)
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Wood, H. TREM-2 signalling and Alzheimer disease — striking the right balance. Nat Rev Neurol 12, 556 (2016). https://doi.org/10.1038/nrneurol.2016.132
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DOI: https://doi.org/10.1038/nrneurol.2016.132
