Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2.
Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2.
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DOI：
10.1186/1750-1326-9-20
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发表时间：
2014-06-03
影响因子：
15.1
通讯作者：
Holtzman DM
中科院分区：
文献类型：
--
作者：
Ulrich JD;Finn MB;Wang Y;Shen A;Mahan TE;Jiang H;Stewart FR;Piccio L;Colonna M;Holtzman DM
最近的全基因组关联研究将 TREM2 变异与患阿尔茨海默病的几率大幅增加联系起来。 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，被认为可以调节小胶质细胞对大脑病理的吞噬和炎症反应。鉴于变异 TREM2 的单个等位基因可能导致功能丧失，从而增加患阿尔茨海默病的风险，我们测试了一个功能性 trem2 等位基因的丧失是否会影响 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。在表达一份或两份 trem2 的 3 个月大或 7 个月大的 APPPS1-21 小鼠中，Aβ 沉积没有显着差异。然而，携带一份 trem2 拷贝的 3 个月大的小鼠表现出斑块相关小胶质细胞的数量和大小显着减少。虽然 3 月龄或 7 月龄动物的细胞因子水平或小胶质细胞活化标志物没有统计学上的显着差异，但与 TREM2+/+ 小鼠相比，3 月龄 TREM2+/- 小鼠中 NOS2、C1qa 和 IL1a 的表达有降低的趋势。 trem2 单个拷贝的丢失对 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 对于小胶质细胞对 Aβ 沉积的反应很重要，但 TREM2 表达减少 50% 不会影响 Aβ 斑块负荷。
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.
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影响因子：
5.8
作者：
Mosher, Kira Irving;Wyss-Coray, Tony
通讯作者：
Wyss-Coray, Tony
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：
10.4049/jimmunol.1102836
发表时间：
2012-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Otero K;Shinohara M;Zhao H;Cella M;Gilfillan S;Colucci A;Faccio R;Ross FP;Teitelbaum SL;Takayanagi H;Colonna M
通讯作者：
Colonna 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：
5.3
作者：
Bondolfi, L;Calhoun, M;Jucker, M
通讯作者：
Jucker, M