Investigation of pathology, expression and proteomic profiles in human TREM2 variant postmortem brains with and without Alzheimer's disease.
Investigation of pathology, expression and proteomic profiles in human TREM2 variant postmortem brains with and without Alzheimer's disease.
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DOI：
10.1111/bpa.12842
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发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Lashley T
中科院分区：
文献类型：
--
作者：
Toomey CE;Heywood W;Benson BC;Packham G;Mills K;Lashley T
髓细胞上表达的触发受体2 TREM2被确定为晚发型阿尔茨海默病（AD）的危险因素。在这里，我们比较了TREM2变异（TREM2+）和没有TREM2变异（TREM2−）的病例，考虑了队列之间的病理负担、炎症反应、典型途径和生化功能的改变。我们假设TREM2+病例会有功能丧失，这表明与TREM2−病例相比，炎症谱发生了改变。在伴有和不伴有AD的TREM2+病例中，使用针对Aβ、tau和小胶质细胞标志物的抗体进行免疫组化，并将其与散发性TREM2−AD、家族性AD和神经正常对照进行比较。除了小胶质细胞负荷和圆度外，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测定表达和蛋白质组学谱。TREM2+对照组无Aβ和tau沉积。在TREM2+和TREM2 - SAD病例中，没有观察到Aβ或tau的数量，或Aβ斑块的组成。不同疾病组间小胶质细胞负荷无差异。然而，TREM2+ SAD病例比TREM2 - SAD病例显示更多的变形虫小胶质细胞，尽管小胶质细胞和β斑块的空间关系没有差异。典型通路和生物学功能的可视化显示了疾病组与正常对照组之间的差异，清楚地显示TREM2+ SAD、TREM2 - SAD和FAD组中许多通路上调，而TREM2+对照病例显示大多数代表性通路下调。这些发现表明，TREM2+对照组虽然携带TREM2+变体，但没有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，TREM2影响小胶质细胞参与疾病发病机制。
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.
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影响因子：
4.2
作者：
Forabosco P;Ramasamy A;Trabzuni D;Walker R;Smith C;Bras J;Levine AP;Hardy J;Pocock JM;Guerreiro R;Weale ME;Ryten M
通讯作者：
Ryten M
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
3.7
作者：
Abduljaleel Z;Al-Allaf FA;Khan W;Athar M;Shahzad N;Taher MM;Elrobh M;Alanazi MS;El-Huneidi W
通讯作者：
El-Huneidi W
DOI：
10.1111/bpa.12564
发表时间：
2018-09
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
Fahrenhold M;Rakic S;Classey J;Brayne C;Ince PG;Nicoll JAR;Boche D;MRC-CFAS
通讯作者：
MRC-CFAS
影响因子：
7.4
作者：
Coats, Caroline J.;Heywood, Wendy E.;Elliott, Perry M.
通讯作者：
Elliott, Perry M.