Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice.
Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice.
复制标题
DOI：
10.1186/s13024-020-00409-0
复制
发表时间：
2020-10-28
影响因子：
15.1
通讯作者：
Lamb BT
中科院分区：
文献类型：
--
作者：
Jadhav VS;Lin PBC;Pennington T;Di Prisco GV;Jannu AJ;Xu G;Moutinho M;Zhang J;Atwood BK;Puntambekar SS;Bissel SJ;Oblak AL;Landreth GE;Lamb BT
髓样细胞上表达的触发受体2（TREM 2）在脑中仅在小胶质细胞上表达，并且遗传变体与包括阿尔茨海默病（AD）、额颞叶痴呆（FTD）和Nasu Hakola病（NHD）的神经退行性疾病相关。Trem 2变体R47 H赋予发展迟发性阿尔茨海默病的显著升高的风险，而NHD连锁的Trem 2变体如Y38 C与具有白色病理的早发性痴呆的发展相关。然而，目前尚不清楚这些Trem 2物种如何使个体易患早老性痴呆。为了研究Trem 2 Y38 C或Trem 2的丧失是否改变神经元功能，我们产生了一种新的小鼠模型，以使用CRISPR/Cas9技术在鼠Trem 2中引入NHD Trem 2 Y38 C变体。Trem 2 Y38 C/Y38 C和Trem 2 −/−小鼠使用生物化学、电生理学和转录组学方法评估Trem 2表达、差异表达基因、突触蛋白水平和突触可塑性。虽然携带Trem 2 Y38 C的小鼠表现出正常的TREM 2表达水平，但在6个月时的病理结果表型模仿了Trem 2 −/−小鼠。转录组学分析显示神经元和少突胶质细胞/髓鞘基因的表达改变。我们观察到突触蛋白水平的区域性下降，海马中受影响最大的突触。这些改变与突触可塑性降低有关。我们的研究结果提供了体内证据，表明Trem 2 Y38 C破坏了正常的TREM 2功能。Trem 2 Y38 C/Y38 C和Trem 2 −/−小鼠在6个月时表现出基因表达改变、小胶质细胞形态改变、突触蛋白丢失和海马突触可塑性降低，而不存在任何病理触发因素，如淀粉样蛋白。这表明TREM 2影响神经元功能，为具有导致早老性痴呆的TREM 2变体的个体的易感性提供分子见解。补充信息随附于10.1186/s13024-020-00409-0。
Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia. Supplementary information accompanies this paper at 10.1186/s13024-020-00409-0.
登录
查看更多内容
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：
7.7
作者：
Harrington, Adam J.;Raissi, Aram;Cowan, Christopher W.
通讯作者：
Cowan, Christopher W.
影响因子：
32.4
作者：
Filipello, Fabia;Morini, Raffaella;Matteoli, Michela
通讯作者：
Matteoli, Michela
影响因子：
15.1
作者：
Bemiller SM;McCray TJ;Allan K;Formica SV;Xu G;Wilson G;Kokiko-Cochran ON;Crish SD;Lasagna-Reeves CA;Ransohoff RM;Landreth GE;Lamb BT
通讯作者：
Lamb BT