Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer's-like cognitive decline
Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer's-like cognitive decline
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DOI：
10.1172/jci66541
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发表时间：
2014-03-01
影响因子：
15.9
通讯作者：
Koronyo-Hamaoui, Maya
中科院分区：
文献类型：
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作者：
Bernstein, Kenneth E.;Koronyo, Yosef;Koronyo-Hamaoui, Maya
阿尔茨海默病(AD)患者的认知能力下降与脑内淀粉样β蛋白(Aβ)水平升高有关，特别是神经毒性Aβ(1-42)。血管紧张素转换酶(ACE)能降解Aβ(1-42)，在粒单核细胞中过表达ACE可增强其免疫功能。为了研究靶向ACE过表达对AD的影响，我们将使用c-FINS启动子在骨髓单核细胞中过表达ACE的ACEW小鼠与AD转基因APP(SWE)/PS1(Delta E9)小鼠模型进行杂交。对这些AD ACE(10/10)小鼠在7个月和13个月时的脑组织评估显示，与AD(+)小鼠相比，可溶和不溶脑Aβ(1-42)的水平都降低了。此外，斑块负担和星形胶质细胞增多症都显著减少。给予血管紧张素转换酶抑制剂雷米普利可使AD(+)ACE(10/10)小鼠的Aβ水平比血管紧张剂肼铝氮非依赖性药物诱导的水平升高。总体而言，AD+ACE(10/10)小鼠的脑组织浸润性细胞较少，这与AD相关病理减少一致，尽管ACE过表达的巨噬细胞在Aβ斑块周围大量表达并吞噬。在11个月和12个月大时，AD‘ACEnVwT和AD AcElop.o小鼠的认知能力实际上与非AD小鼠相同，通过迷宫行为测试进行评估。我们的数据表明，增强的免疫反应，加上具有催化活性的血管紧张素转换酶单核细胞表达的增加，可以防止AD小鼠模型的认知能力下降。
Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of am.yloid beta protein (A beta), particularly neurotoxic A beta(1-42). Angiotensin-converting enzyme (ACE) can degrade A beta(1-42), and ACE overexpression in myelomonocydc cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACEW mice, which overexpress ACE in myelomonocytes using the c-fins promoter, with the transgenic APP(SWE)/PS1(Delta E9) mouse model of AD (AD). Evaluation of brain tissue from these AD ACE(10/10)- mice at 7 and 13 months revealed that levels of both soluble and insoluble brain A beta(1-42) were reduced compared with those in AD(+) mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased A beta levels in AD(+)ACE(10/10) mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, AD+ACE(10/10) mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing A beta plaques. At 11 and 12 months of age, the AD'ACEnVwT and AD AcElop.o mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocydc expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.