Triggering receptor expressed on myeloid cells 2 TREM2 was identified as a risk factor for late onset Alzheimer’s disease (AD). Here we compared TREM2 cases with a variant (TREM2⁺) and cases without a TREM2 variant (TREM2⁻ ), considering pathological burden, inflammatory response and altered canonical pathways and biochemical functions between the cohorts. We hypothesised that TREM2⁺ cases would have a loss of function, indicating an altered inflammatory profile compared to TREM2⁻ cases. Immunohistochemistry was performed using antibodies against Aβ, tau and microglia markers in TREM2⁺ cases, with and without AD, which were compared to sporadic TREM2⁻ AD, familial AD and neurologically normal control cases. Aβ and tau load were measured along with the composition of Aβ plaques, in addition to microglial load and circularity. Expression and proteomic profiles were determined from the frontal cortex of selected cases. TREM2⁺ control cases had no Aβ or tau deposition. No differences in the amount of Aβ or tau, or the composition of Aβ plaques were observed between TREM2⁺ and TREM2⁻ SAD cases. There were no differences in microglial load observed between disease groups. However, the TREM2⁺ SAD cases showed more amoeboid microglia than the TREM2⁻ SAD cases, although no differences in the spatial relationship of microglia and Aβ plaques were identified. Visualisation of the canonical pathways and biological functions showed differences between the disease groups and the normal controls, clearly showing a number of pathways upregulated in TREM2⁺ SAD, TREM2⁻ SAD and FAD groups whilst, the TREM2⁺ controls cases showed a downregulation of the majority of the represented pathways. These findings suggest that the TREM2⁺ control group, although carrying the TREM2⁺ variant, have no pathological hallmarks of AD, have altered microglial and expression profiles compared to the TREM2⁺ SAD cases. This indicates that other unknown factors may initiate the onset of AD, with TREM2 influencing the microglial involvement in disease pathogenesis.

中文翻译：

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对患有和不患有阿尔茨海默病的人类 TREM2 变异死后大脑的病理学、表达和蛋白质组学特征的研究。

在骨髓细胞上表达的触发受体 2 TREM2被确定为晚发性阿尔茨海默病 (AD) 的危险因素。在这里，我们比较了具有变异 ( TREM2 ⁺ ) 的TREM2病例和没有TREM2变异的病例( TREM2 ^- )，同时考虑了队列之间的病理负担、炎症反应和改变的典型途径和生化功能。我们假设TREM2 ⁺病例会丧失功能，表明与TREM2 ^-病例相比炎症特征发生了改变。使用针对 Aβ、tau 和小胶质细胞标记物的抗体进行免疫组织化学 TREM2 ⁺ 病例，有和没有 AD，与散发性TREM2 ^- AD、家族性 AD 和神经学正常对照病例进行比较。除了小胶质细胞负荷和圆形度外，还测量了 Aβ 和 tau 负荷以及 Aβ 斑块的组成。从选定病例的额叶皮层确定表达和蛋白质组学特征。TREM2 ⁺ 对照病例没有 Aβ 或 tau 沉积。在TREM2 ⁺ 和TREM2 ^- SAD 病例之间没有观察到 Aβ 或 tau 的量或 Aβ 斑块的组成存在差异。在疾病组之间观察到的小胶质细胞负荷没有差异。然而，TREM2 ⁺ SAD 病例显示出比TREM2 ^- SAD 病例更多的变形虫小胶质细胞，尽管小胶质细胞和 Aβ 斑块的空间关系没有差异。经典通路和生物学功能的可视化显示疾病组和正常对照之间存在差异，清楚地显示了TREM2 ⁺ SAD、TREM2 ^- SAD 和 FAD 组中的许多通路上调，而TREM2 ⁺ 对照病例显示出大多数的下调所代表的路径。这些发现表明TREM2 ⁺ 对照组虽然携带TREM2 ⁺ 变体，没有 AD 的病理特征，与TREM2 ⁺ SAD 病例相比，小胶质细胞和表达谱发生了改变。这表明其他未知因素可能引发 AD 的发病，其中TREM2影响小胶质细胞参与疾病发病机制。