Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Mol Neurodegener. 2014 Jun 3;9:20. doi: 10.1186/1750-1326-9-20.
Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer's disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer's disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer's disease, we tested whether loss of one functional trem2 allele would affect Aβ plaque deposition or the microglial response to Aβ pathology in APPPS1-21 mice.
There was no significant difference in Aβ deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2+/- vs. TREM2+/+ mice.
Loss of a single copy of trem2 had no effect on Aβ pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aβ deposition but that a 50% decrease inTREM2 expression does not affect Aβ plaque burden.
最近的全基因组关联研究将 TREM2 变异与阿尔茨海默病发病风险的大幅增加联系起来。TREM2 影响阿尔茨海默病易感性的机制目前尚不清楚。TREM2 由小胶质细胞表达，被认为调节小胶质细胞对脑病理学的吞噬和炎症反应。鉴于变异 TREM2 的一个等位基因，可能导致功能丧失，增加了患阿尔茨海默病的风险，我们测试了缺失一个功能性 trem2 等位基因是否会影响 APPPS1-21 小鼠中的 Aβ 斑块沉积或小胶质细胞对 Aβ 病理学的反应。
在表达一个或两个 trem2 拷贝的 3 个月或 7 个月大的 APPPS1-21 小鼠中，Aβ 沉积没有显著差异。然而，携带一个 trem2 拷贝的 3 个月大的小鼠中，斑块相关小胶质细胞的数量和大小明显减少。虽然 3 个月和 7 个月大的动物中细胞因子水平或小胶质细胞激活标志物没有统计学上的显著差异，但在 TREM2+/-与 TREM2+/+ 小鼠中，NOS2、C1qa 和 IL1a 的表达呈下降趋势。
缺失一个 trem2 拷贝对 Aβ 病理学没有影响，但改变了斑块相关小胶质细胞的形态表型。这些数据表明 TREM2 对小胶质细胞对 Aβ 沉积的反应很重要，但 TREM2 表达减少 50%不会影响 Aβ 斑块负担。
