Blocking TGF-β-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology
Blocking TGF-β-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology
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DOI：
10.1038/nm1781
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发表时间：
2008-06-01
期刊：
影响因子：
82.9
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
--
作者：
Town, Terrence;Laouar, Yasmina;Flavell, Richard A.
阿尔茨海默病是最常见的痴呆症，其病理特征是淀粉样蛋白- β肽（A β）沉积到β -淀粉样斑块，神经元损伤和低水平的慢性脑免疫激活(1)。转化生长因子- β s （tgf - β s）是一种多效细胞因子，在免疫细胞激活、炎症和损伤后修复中起关键作用(2)。我们通过在C57BL/6小鼠（CD11c- dnr）中诱导CD11c启动子驱动的显性阴性tgf - β受体II型的表达，从遗传上中断先天免疫细胞中的tgf - β和下游Smad2/3信号（tgf - β -Smad2/3）(3)，将这些小鼠与过表达突变的人淀粉样前体蛋白的小鼠Tg2576阿尔茨海默病小鼠模型(4)杂交，并评估阿尔茨海默病样病理。老年双转基因小鼠显示tg2576相关的多动症完全缓解，空间工作记忆缺陷部分缓解。Tg2576-CD11c-DNR小鼠脑实质和脑血管β -淀粉样蛋白沉积和A - β丰度显著（高达90%）减弱。这与脑血管周围含有A β的外周巨噬细胞和β -淀粉样斑块的浸润增加有关。体外培养的CD11c-DNR小鼠外周巨噬细胞，而非小胶质细胞，显示经典tgf - β激活的Smad2/3被阻断，但也显示替代骨形态发生蛋白激活的Smad1/5/8信号被过度激活，A β吞噬增加。药理抑制激活素样激酶-5（一种I型tgf - β受体）后也发现了类似的效果。综上所述，我们的研究结果表明，阻断外周巨噬细胞中的tgf - β - smad2 /3信号是治疗阿尔茨海默病的新靶点。
Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-beta peptide (A beta) into beta-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity(1). Transforming growth factor-beta s (TGF-beta s) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury(2). We genetically interrupted TGF-beta and downstream Smad2/3 signaling (TGF-beta-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-beta receptor type II in C57BL/6 mice (CD11c-DNR)(3), crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model(4), and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular beta-amyloid deposits and A beta abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of A beta-containing peripheral macrophages around cerebral vessels and beta-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-beta activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smad1/5/8 signaling and increased A beta phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-beta receptor. Taken together, our results suggest that blockade of TGF-beta-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease.