Song Wilbur, Hooli Basavaraj, Mullin Kristina, Jin Sheng Chih, Cella Marina, Ulland Tyler K, Wang Yaming, Tanzi Rudolph E, Colonna Marco
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Neurology, Harvard Medical School, and Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA, USA.
Alzheimers Dement. 2017 Apr;13(4):381-387. doi: 10.1016/j.jalz.2016.07.004. Epub 2016 Aug 9.
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.
TREM2是小胶质细胞上一种感知脂质的激活受体，已知对阿尔茨海默病（AD）很重要，但它在疾病发病机制中起有益还是有害作用存在争议。
我们在国立精神卫生研究所AD遗传学倡议研究和AD测序项目中分析了TREM2变异体的AD风险。我们通过报告基因检测比较了每个变异体的风险和功能影响。最后，我们分析了TREM2在人单核细胞上的表达。
我们提供了更多证据表明几种TREM2变异体与AD风险增加相关，并表明这些变异体减少或显著增加了与TREM2配体的结合。我们确定高密度脂蛋白（HDL）和低密度脂蛋白（LDL）为新型TREM2配体。我们还表明，与单核细胞衍生的树突状细胞相比，人单核细胞中TREM2的表达极少。
我们的结果表明，TREM2信号传导有助于预防AD，但过度时可能会造成损害，支持了适当的TREM2功能对于对抗疾病进展很重要的观点。
