Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.

中文翻译：

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抗体介导的人小胶质细胞白细胞 Ig 样受体 B4 的靶向可减轻小鼠模型中的淀粉样蛋白病理学

小胶质细胞通过限制淀粉样蛋白-β (Aβ) 病理学来帮助限制阿尔茨海默病 (AD) 的进展，而淀粉样蛋白-β (Aβ) 病理学是通过不同细胞表面受体传递的激活和抑制性细胞内信号的平衡来实现的。人白细胞 Ig 样受体 B4 (LILRB4) 是免疫球蛋白 (Ig) 超家族的抑制性受体，在骨髓细胞上表达，可识别载脂蛋白 E (ApoE) 以及其他配体。在这里，我们发现 LILRB4 在 AD 患者的小胶质细胞中高表达。使用积累 Aβ 并携带包含LILRB4的LILR区域一部分的转基因的小鼠，我们证实了包裹 Aβ 斑块的小胶质细胞中丰富的 LILRB4 表达。用抗人 LILRB4 单克隆抗体 (mAb) 对这些小鼠进行全身治疗，可减少 Aβ 负荷，减轻一些 Aβ 相关行为异常，增强小胶质细胞活性，并减弱干扰素诱导基因的表达。体外结合实验证实，人 LILRB4 可以结合人和小鼠 ApoE，并且抗人 LILRB4 mAb 可以阻断这种相互作用。在计算机建模、生化和诱变分析中，确定了与小鼠 ApoE 相互作用所需的 LILRB4 两个胞外 Ig 结构域之间的环，并进一步表明抗 LILRB4 mAb 可能通过直接结合该环来阻断 LILRB4-mApoE。因此，靶向LILRB4可能是AD的潜在治疗途径。