The role of ADAM17 in cerebrovascular and cognitive function in the APP/PS1 mouse model of Alzheimer's disease.
The role of ADAM17 in cerebrovascular and cognitive function in the APP/PS1 mouse model of Alzheimer's disease.
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DOI：
10.3389/fnmol.2023.1125932
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发表时间：
2023
影响因子：
4.8
通讯作者：
Bagi, Zsolt
中科院分区：
文献类型：
--
作者：
Tian, Yanna;Fopiano, Katie Anne;Buncha, Vadym;Lang, Liwei;Suggs, Hayden A.;Wang, Rongrong;Rudic, R. Daniel;Filosa, Jessica A.;Bagi, Zsolt
关键词：
去整合素和金属蛋白酶17具有α分泌酶活性，从而阻止神经毒性淀粉样前体蛋白-α(APP)的产生。ADAM17在血管内皮细胞中大量表达，可能参与调节血管内稳态反应，包括血管运动功能、血管壁形态和新血管的形成。血管ADAM17在神经退行性疾病中的作用仍然知之甚少。在这里，我们假设脑血管ADAM17在阿尔茨海默病(AD)的发病机制中发挥作用。我们发现，9-10月龄的APP/PS1小鼠患有b-淀粉样蛋白积聚和短期记忆和认知障碍，其脑微血管中ADAM17的表达显著减少。系统递送和腺相关病毒(AAV)介导的ADAM17在APP/PS1小鼠中的重新表达改善了认知功能，而不影响b-淀粉样斑块密度。与WT小鼠相比，APP/PS1小鼠的分离和加压脑动脉对乙酰胆碱的内皮依赖性扩张显著降低，而对一氧化氮供体硝普钠的血管平滑肌依赖性扩张保持不变。ADAM17基因的重新表达可使APP/PS1小鼠受损的内皮依赖性血管扩张功能恢复到正常水平。ADAM17基因的重新表达不影响APP/PS1小鼠的脑动脉生物力学特性(壁应力和弹性)和微血管网络密度。此外，蛋白质组学分析发现，几个差异表达的分子参与了AD神经退变和神经元修复机制，这些机制被ADAM17重新表达逆转。因此，我们认为ADAM17在脑微血管中的表达减少损害了血管扩张功能，这可能是导致APP/PS1小鼠认知功能障碍的原因之一，ADAM17有可能成为治疗AD的靶点。
The disintegrin and metalloproteinase 17 (ADAM17) exhibits α-secretase activity, whereby it can prevent the production of neurotoxic amyloid precursor protein-α (APP). ADAM17 is abundantly expressed in vascular endothelial cells and may act to regulate vascular homeostatic responses, including vasomotor function, vascular wall morphology, and formation of new blood vessels. The role of vascular ADAM17 in neurodegenerative diseases remains poorly understood. Here, we hypothesized that cerebrovascular ADAM17 plays a role in the pathogenesis of Alzheimer’s disease (AD). We found that 9-10 months old APP/PS1 mice with b-amyloid accumulation and short-term memory and cognitive deficits display a markedly reduced expression of ADAM17 in cerebral microvessels. Systemic delivery and adeno-associated virus (AAV)-mediated re-expression of ADAM17 in APP/PS1 mice improved cognitive functioning, without affecting b-amyloid plaque density. In isolated and pressurized cerebral arteries of APP/PS1 mice the endothelium-dependent dilation to acetylcholine was significantly reduced, whereas the vascular smooth muscle-dependent dilation to the nitric oxide donor, sodium nitroprusside was maintained when compared to WT mice. The impaired endothelium-dependent vasodilation of cerebral arteries in APP/PS1 mice was restored to normal level by ADAM17 re-expression. The cerebral artery biomechanical properties (wall stress and elasticity) and microvascular network density was not affected by ADAM17 re-expression in the APP/PS1 mice. Additionally, proteomic analysis identified several differentially expressed molecules involved in AD neurodegeneration and neuronal repair mechanisms that were reversed by ADAM17 re-expression. Thus, we propose that a reduced ADAM17 expression in cerebral microvessels impairs vasodilator function, which may contribute to the development of cognitive dysfunction in APP/PS1 mice, and that ADAM17 can potentially be targeted for therapeutic intervention in AD.
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发表时间：
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影响因子：
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作者：
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