Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease
Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease
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DOI：
10.1007/s00401-019-02013-z
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发表时间：
2019-08-01
影响因子：
12.7
通讯作者：
Deierborg, Tomas
中科院分区：
文献类型：
--
作者：
Boza-Serrano, Antonio;Ruiz, Rocio;Deierborg, Tomas
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其中淀粉样β（Aβ）肽的细胞外聚集体形成、神经元内tau蛋白的纤维缠结以及小胶质细胞激活是主要的病理特征。参与小胶质细胞激活的关键分子之一是半乳糖凝集素 - 3（gal3），我们在此首次证明了gal3在AD病理中的关键作用。gal3在AD患者和5xFAD（家族性阿尔茨海默病）小鼠的大脑中高度上调，并且发现其在与Aβ斑块相关的小胶质细胞中特异性表达。编码gal3的LGALS3基因中的单核苷酸多态性与AD风险增加相关。在5xFAD小鼠中缺失gal3可减弱与小胶质细胞相关的免疫反应，特别是那些与Toll样受体（TLR）和TREM2/DAP12信号通路相关的免疫反应。体外数据显示，gal3是小胶质细胞对纤维状Aβ完全激活所必需的。gal3缺失降低了5xFAD小鼠中的Aβ负荷并改善了认知行为。有趣的是，在野生型（WT）小鼠海马内单次注射gal3以及Aβ单体足以诱导形成持久的（2个月）不溶性Aβ聚集体，而当缺乏gal3时则不会形成。高分辨率显微镜（随机光学重建显微镜）显示gal3和TREM2在小胶质细胞突起中紧密共定位，并且通过涉及gal3碳水化合物识别结构域的荧光各向异性测定显示了它们之间的直接相互作用。此外，gal3被证明可刺激报告细胞系中的TREM2 - DAP12信号通路。总体而言，我们的数据支持这样的观点，即抑制gal3可能是一种对抗AD的潜在药理学方法。
Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (A beta) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with A beta plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar A beta. Gal3 deletion decreased the A beta burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with A beta monomers in WT mice was sufficient to induce the formation of long-lasting (2months) insoluble A beta aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2-DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.