Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-β1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (∼3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-β1-42, vascular and parenchymal amyloid-β deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-β plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and ∼60% lower tumour necrosis factor-α (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-β1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-β1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-β conformers as well as substantially more effective amyloid-β1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and ∼80% increased extracellular degradation of amyloid-β1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-α), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer's-related amyloid-β1-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-β forms.

中文翻译：

---

外周来源的血管紧张素转化酶增强的巨噬细胞可缓解阿尔茨海默病相关疾病。

将血管紧张素转化酶（ACE）（一种淀粉样β蛋白降解酶）靶向过表达到脑部驻留的小胶质细胞和外周骨髓单核细胞（ACE10模型），可在双转基因APPSWE /PS1ΔE9（AD +）小鼠中大大减轻阿尔茨海默氏病。在这项研究中，我们探讨了选择性和短暂性血管紧张素转化酶过表达对巨噬细胞行为的影响以及骨髓来源的ACE10巨噬细胞（而非小胶质细胞）在减缓疾病进展中的相对作用。为此，在AD +小鼠中应用了两种体内方法：（i）带头罩的ACE10 / GFP +骨髓移植；（ii）CD115 + -ACE10 / GFP +单核细胞过继转移至外周血。进一步进行了广泛的体外研究，以建立对淀粉样蛋白-β1-42原纤维和寡聚体的响应的独特的ACE10-巨噬细胞表型。体内结合方法显示，与野生型单核细胞相比，ACE10的脑浸润增加（增加约3倍； P <0.05）导致脑可溶性淀粉样蛋白β1-42，血管和实质淀粉样蛋白β沉积物减少，和星形细胞增多症（分别为31％，47-80％和33％； P <0.05-0.0001）。ACE10巨噬细胞围绕脑和视网膜淀粉样蛋白-β斑块，并表达高3.2倍的胰岛素样生长因子-1（P <0.01）和低约60％的肿瘤坏死因子-α（P <0.05）。重要的是，有症状的AD +小鼠中CD115 + -ACE10单核细胞的血液富集导致明显的突触和认知保存（P <0.05-0.001）。巨噬细胞对定义明确的淀粉样β1-42构象异构体（原纤维，病毒棒状结构和稳定的可溶性寡聚体）的体外分析表明，ACE10巨噬细胞对淀粉样β1-42物种具有广泛的抗性。它们显示出与淀粉样β-构象异构体的表面结合增加了2-5倍，并且淀粉样β-1-42摄取更有效，比相关的野生型巨噬细胞高至少8倍（P <0.0001）。具有表面清除​​剂受体（即CD36，清除剂受体A类1成员）的表达增强，在髓样细胞2，CD163上表达的触发受体； P <0.05-0.0001），内体加工（P <0.05-0.0001），并且增加约80％淀粉样蛋白β1-42的细胞外降解（P <0.001）。有益的ACE10表型被血管紧张素转化酶抑制剂（赖诺普利）逆转，因此取决于血管紧张素转化酶的催化活性。此外，即使在暴露于阿尔茨海默氏症后，ACE10巨噬细胞也具有独特的抗炎作用（低诱导型一氧化氮合酶和较低的肿瘤坏死因子-α），促愈的免疫特征（胰岛素样生长因子-1高，细胞形态延长）。相关的淀粉样蛋白-β1-42寡聚体。总体而言，我们为血管紧张素转换酶过表达的巨噬细胞在保留突触和认知，减轻神经病理学和神经炎症以及增强对确定的病理神经淀粉样β形式的耐药性方面的治疗作用提供了第一个证据。ACE10巨噬细胞即使暴露于阿尔茨海默氏症相关的淀粉样蛋白，也具有独特的抗炎作用（低诱导型一氧化氮合酶和较低的肿瘤坏死因子-α），有利于治愈的免疫特征（胰岛素样生长因子-1高，细胞形态延长）。 -β1-42低聚物。总体而言，我们为血管紧张素转换酶过表达的巨噬细胞在保留突触和认知，减轻神经病理学和神经炎症以及增强对确定的病理神经淀粉样β形式的耐药性方面的治疗作用提供了第一个证据。ACE10巨噬细胞即使在暴露于阿尔茨海默氏症相关的淀粉样蛋白后，仍具有独特的抗炎作用（低诱导型一氧化氮合酶和较低的肿瘤坏死因子-α），有利于治愈的免疫特征（高胰岛素样生长因子-1，延长的细胞形态）。 -β1-42低聚物。总体而言，我们为血管紧张素转换酶过表达的巨噬细胞在保持突触和认知，减轻神经病理学和神经炎症以及增强对确定的病理神经淀粉样β形式的耐药性方面的治疗作用提供了第一个证据。s相关淀粉样蛋白-β1-42低聚物。总体而言，我们为血管紧张素转换酶过表达的巨噬细胞在保留突触和认知，减轻神经病理学和神经炎症以及增强对确定的病理神经淀粉样β形式的耐药性方面的治疗作用提供了第一个证据。s相关淀粉样蛋白-β1-42低聚物。总体而言，我们为血管紧张素转换酶过表达的巨噬细胞在保留突触和认知，减轻神经病理学和神经炎症以及增强对确定的病理神经淀粉样β形式的耐药性方面的治疗作用提供了第一个证据。