Intranasal Lactoferrin Enhances α-Secretase-Dependent Amyloid Precursor Protein Processing via the ERK1/2-CREB and HIF-1α Pathways in an Alzheimer's Disease Mouse Model
Intranasal Lactoferrin Enhances α-Secretase-Dependent Amyloid Precursor Protein Processing via the ERK1/2-CREB and HIF-1α Pathways in an Alzheimer's Disease Mouse Model
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在阿尔茨海默病小鼠模型中，鼻内乳铁蛋白通过 ERK1/2-CREB 和 HIF-1 α 通路增强 α 分泌酶依赖性淀粉样前体蛋白加工
DOI：
10.1038/npp.2017.8
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发表时间：
2017-12-01
影响因子：
7.6
通讯作者：
Wang, Zhan-You
中科院分区：
文献类型：
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作者：
Guo, Chuang;Yang, Zhao-Hui;Wang, Zhan-You
越来越多的证据表明，乳铁蛋白(LF)是一种铁结合糖蛋白，是一种多功能营养物质。此外，LF最近被认为是一种神经保护剂。这些特性使LF成为治疗阿尔茨海默病(AD)的有价值的候选药物。然而，在阿尔茨海默病的病理状态中，调节LF生理作用的机制仍不清楚。本研究采用APPswe/PS1DE9转基因AD小鼠模型。在这个AD模型中，我们探索了鼻腔内注射人低分子肝素(HLF)是否可以减少β-淀粉样蛋白(Aβ)的沉积并改善认知功能下降。我们发现，HLF通过激活α-分泌酶a-去整合素和金属蛋白酶10(ADAM10)，促进淀粉样前体蛋白(APP)加工的非淀粉样代谢，导致APP的α-COOH末端片段被增强切割，相应的NH2-末端APP产物可溶性APP-α(SAPPα)升高，从而减少Aβ生成，改善AD小鼠的空间认知学习能力。为了深入了解LF调控APP加工的分子机制，我们评估了稳定转染瑞典突变人APP的N2a细胞(APPsw N2a细胞)中APP切割的关键分子和信号通路的参与。结果表明，HLF可激活ERK1/2-CREB和HIF-1α信号通路，从而诱导ADAM10的表达。在暗示HLF作为抗氧化剂和抗炎的潜在用途之前，还进行了额外的测试。这些发现为HLF通过激活ERK1/2-CREB和HIF-1α依赖的ADAM10表达抑制AD认知功能下降的来源和机制提供了新的见解。
Growing evidence suggests that lactoferrin (Lf), an iron-binding glycoprotein, is a pleiotropic functional nutrient. In addition, Lf was recently implicated as a neuroprotective agent. These properties make Lf a valuable therapeutic candidate for the treatment of Alzheimer's disease (AD). However, the mechanisms regulating the physiological roles of Lf in the pathologic condition of AD remain unknown. In the present study, an APPswe/PS1DE9 transgenic mouse model of AD was used. We explored whether intranasal human Lf (hLf) administration could reduce beta-amyloid (A beta) deposition and ameliorate cognitive decline in this AD model. We found that hLf promoted the non-amyloidogenic metabolism of amyloid precursor protein (APP) processing through activation of alpha-secretase a-disintegrin and metalloprotease10 (ADAM10), resulting in enhanced cleavage of the alpha-COOH-terminal fragment of APP and the corresponding elevation of the NH2-terminal APP product, soluble APP-alpha (sAPP alpha), which consequently reduced A beta generation and improved spatial cognitive learning ability in AD mice. To gain insight into the molecular mechanism by which Lf modulates APP processing, we evaluated the involvement of the critical molecules for APP cleavage and the signaling pathways in N2a cells stably transfected with Swedish mutant human APP (APPsw N2a cells). The results show that the ERK1/2-CREB and HIF-1 alpha signaling pathways were activated by hLf treatment, which is responsible for the expression of induced ADAM10. Additional tests were performed before suggesting the potential use of hLf as an antioxidant and anti-inflammatory. These findings provide new insights into the sources and mechanisms by which hLf inhibits the cognitive decline that occurs in AD via activation of ADAM10 expression in an ERK1/2-CREB and HIF-1 alpha-dependent manner.