Gomez Andrew R, Byun Hyae Ran, Wu Shaogen, Muhammad A K M Ghulam, Ikbariyeh Jasmine, Chen Jaelin, Muro Alek, Li Lin, Bernstein Kenneth E, Ainsworth Richard, Tourtellotte Warren G
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Nat Aging. 2025 Jun 9. doi: 10.1038/s43587-025-00879-1.
Genome-wide association studies have identified many gene polymorphisms associated with an increased risk of developing late-onset Alzheimer's disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing innate immune responses and lipid metabolism of microglia (MG). Here we show that boosting the expression of angiotensin-converting enzyme (ACE), a genome-wide association study LOAD risk-associated gene product, specifically in MG, reduces amyloid-β (Aβ) plaque load, preserves vulnerable neurons and excitatory synapses, and significantly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of AD. ACE-expressing MG surround plaques more frequently and they have increased Aβ phagocytosis, endolysosomal trafficking and spleen tyrosine kinase activation downstream of the major Aβ receptors, triggering receptor expressed on myeloid cells 2 (Trem2) and C-type lectin domain family 7 member A (Clec7a). These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing MG as a cell-based therapy to augment endogenous microglial responses to Aβ in AD.
全基因组关联研究已经确定了许多与晚发性阿尔茨海默病（LOAD）发病风险增加相关的基因多态性。其中许多与LOAD风险相关的等位基因通过影响小胶质细胞（MG）的固有免疫反应和脂质代谢来改变疾病发病机制。在这里，我们表明，提高血管紧张素转换酶（ACE）的表达，一种全基因组关联研究中与LOAD风险相关的基因产物，特别是在MG中，可减少淀粉样β（Aβ）斑块负荷，保护脆弱的神经元和兴奋性突触，并显著减少AD的5xFAD淀粉样小鼠模型中的学习和记忆异常。表达ACE的MG更频繁地围绕斑块，并且它们在主要Aβ受体下游具有增加的Aβ吞噬作用、内溶酶体运输和脾酪氨酸激酶激活，触发髓系细胞2（Trem2）和C型凝集素结构域家族7成员A（Clec7a）上表达的受体。这些发现确立了ACE在增强小胶质细胞免疫功能中的作用，并且它们确定了表达ACE的MG作为一种基于细胞的疗法的潜在用途，以增强内源性小胶质细胞对AD中Aβ的反应。
