Danziger Ron, Fuchs Dieu-Trang, Koronyo Yosef, Rentsendorj Altan, Sheyn Julia, Hayden Eric Y, Teplow David B, Black Keith L, Fuchs Sebastien, Bernstein Kenneth E, Koronyo-Hamaoui Maya
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical center, Los Angeles, CA, United States.
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Front Physiol. 2023 Jun 23;14:1179315. doi: 10.3389/fphys.2023.1179315. eCollection 2023.
This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115 myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque. We further demonstrated that introducing ACE10 myelomonocytes (microglia and peripheral monocytes) into the double transgenic APP/PS1 murine model of AD (AD mice), diminished neuropathology and enhanced the cognitive functions. These beneficial effects were dependent on ACE catalytic activity and vanished when ACE was pharmacologically blocked. Moreover, we revealed that the therapeutic effects in AD mice can be achieved by enhancing ACE expression in bone marrow (BM)-derived CD115 monocytes alone, without targeting central nervous system (CNS) resident microglia. Following blood enrichment with CD115 ACE10-monocytes versus wild-type (WT) monocytes, AD mice had reduced cerebral vascular and parenchymal Aβ burden, limited microgliosis and astrogliosis, as well as improved synaptic and cognitive preservation. CD115 ACE10-versus WT-monocyte-derived macrophages (Mo/MΦ) were recruited in higher numbers to the brains of AD mice, homing to Aβ plaque lesions and exhibiting a highly Aβ-phagocytic and anti-inflammatory phenotype (reduced TNFα/iNOS and increased MMP-9/IGF-1). Moreover, BM-derived ACE10-Mo/MΦ cultures had enhanced capability to phagocytose Aβ fibrils, prion-rod-like, and soluble oligomeric forms that was associated with elongated cell morphology and expression of surface scavenger receptors (i.e., CD36, Scara-1). This review explores the emerging evidence behind the role of ACE in AD, the neuroprotective properties of monocytes overexpressing ACE and the therapeutic potential for exploiting this natural mechanism for ameliorating AD pathogenesis.
本综述探讨了血管紧张素转换酶（ACE）在阿尔茨海默病（AD）中的作用及其潜在治疗价值。已知ACE可降解与AD密切相关的神经毒性42个氨基酸长的淀粉样β蛋白（Aβ）异构体。先前在小鼠中的研究表明，在CD115骨髓单核细胞中靶向过表达ACE（ACE10模型）可改善其免疫反应，有效减少病毒和细菌感染、肿瘤生长及动脉粥样硬化斑块。我们进一步证明，将ACE10骨髓单核细胞（小胶质细胞和外周单核细胞）引入AD的双转基因APP/PS1小鼠模型（AD小鼠）中，可减轻神经病理学变化并增强认知功能。这些有益作用依赖于ACE的催化活性，当ACE被药物阻断时则消失。此外，我们发现仅通过增强骨髓（BM）来源的CD115单核细胞中的ACE表达，而不靶向中枢神经系统（CNS）驻留的小胶质细胞，就可以在AD小鼠中实现治疗效果。用CD115 ACE10单核细胞而非野生型（WT）单核细胞富集血液后，AD小鼠的脑血管和实质Aβ负担减轻，小胶质细胞增生和星形胶质细胞增生受限，突触和认知功能也得到改善。与WT单核细胞相比，更多的CD115 ACE10单核细胞衍生的巨噬细胞（Mo/MΦ）被招募到AD小鼠的大脑中，聚集在Aβ斑块病变处，并表现出高度的Aβ吞噬和抗炎表型（TNFα/iNOS减少，MMP-9/IGF-1增加）。此外，BM来源的ACE10-Mo/MΦ培养物吞噬Aβ原纤维、朊病毒杆状和可溶性寡聚体形式的能力增强，这与细胞形态延长和表面清道夫受体（即CD36、Scara-1）的表达有关。本综述探讨了ACE在AD中作用背后的新证据、过表达ACE的单核细胞的神经保护特性以及利用这一自然机制改善AD发病机制的治疗潜力。
