Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease.
Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease.
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DOI：
10.1042/an20100010
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发表时间：
2010-07-12
期刊：
影响因子：
4.7
通讯作者：
Carson MJ
中科院分区：
文献类型：
--
作者：
Melchior B;Garcia AE;Hsiung BK;Lo KM;Doose JM;Thrash JC;Stalder AK;Staufenbiel M;Neumann H;Carson MJ
目前正在研究基于疫苗的自身免疫（抗淀粉样蛋白）治疗在阿尔茨海默病中的治疗潜力。在本研究中，我们研究了淀粉样蛋白病理学的转基因模型中，先前涉及降低自身免疫反应严重程度的两种分子的表达：TREM 2（髓样细胞2上表达的触发受体）和细胞内耐受相关转录物Tmem 176 b（跨膜结构域蛋白176 b）。原位杂交分析表明，这两种分子在斑块相关的小胶质细胞中高度表达，但它们的表达定义了两个不同的斑块相关激活区。Tmem 176 b在淀粉样斑块的内区表达最高，而TREM 2在外区表达最高。TREM 2的诱导表达与硫嘌呤-S阳性淀粉样蛋白沉积物的检测同时发生。转染研究显示，TREM 2的表达与运动性呈负相关，但与小胶质细胞刺激CD 4 + T细胞增殖、TNF（肿瘤坏死因子）和CCL 2（趋化因子配体2）产生的能力呈正相关，但与IFNγ（干扰素γ）产生无关。TREM 2表达与未活化细胞的淀粉样蛋白吞噬作用呈正相关。然而，用LPS（脂多糖）而不是IFNγ激活细胞降低了TREM 2表达与吞噬作用之间的相关性。将Tmem 176 b转染到小胶质细胞和巨噬细胞系中增加了凋亡。总之，这些数据表明，在体内，Tmem 176 b+细胞在最接近的贴壁淀粉样蛋白可能是最不能够清除淀粉样蛋白。相反，斑块外区上的吞噬性TREM 2+小胶质细胞被定位成捕获并将自身抗原呈递给CNS（中枢神经系统）浸润淋巴细胞，而不促进促炎淋巴细胞应答。相反，斑块相关的TREM 2+小胶质细胞有可能引起神经保护性免疫应答，这可能有助于在促炎性抗淀粉样蛋白免疫治疗期间支持CNS功能。
Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred co-incident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4+ T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo, Tmem176b+ cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2+ microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2+ microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies.