Blocking α1 Adrenergic Receptor as a Novel Target for Treating Alzheimer’s Disease

IF 5.4 3区材料科学 Q2 CHEMISTRY, PHYSICAL

ACS Applied Energy Materials Pub Date : 2024-09-26 DOI:10.1021/acschemneuro.4c0041110.1021/acschemneuro.4c00411

Xidong Pan, Zhifeng Lei, Jiang Chen, Congcong Jia, Jie Deng, Ying Liu, Xingmei Luo, Likun Wang, Dan Zi, Zhen Wang*, Song Li* and Jun Tan*,

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Abstract

While amyloidopathy and tauopathy have been recognized as hallmarks in Alzheimer’s disease (AD) brain, recently, increasing lines of evidence have supported the pathological roles of cerebrovascular changes in the pathogenesis and progression of AD. Restoring or ameliorating the impaired cerebrovascular function during the early phase of the disease may yield benefits against the cognitive decline in AD. In the present study, we evaluated the potential therapeutic effects of nicergoline [NG, a well-known α1 adrenergic receptor (ADR) blocker and vasodilator] against AD through ameliorating vascular abnormalities. Our in vitro data revealed that NG could reverse β-amyloid_1–42 (Aβ_1–42)-induced PKC/ERK1/2 activation, the downstream pathway of α1-ADR activation, in α1-ADR-overexpressed N2a cells. NG also blocked Aβ_1–42- or phenylephrine-induced constrictions in isolated rat arteries. All these in vitro data may suggest ADR-dependent impacts of Aβ on vascular function and the reversal effect of NG. In addition, the ameliorating impacts of NG treatment on cerebral vasoconstriction, vasoremodeling, and cognitive decline were investigated in vivo in a PSAPP transgenic AD mouse model. Consistent with in vitro findings, the chronic treatment of NG significantly ameliorated the cerebrovascular dysfunctions and Aβ plaque depositions in the brain. Moreover, an improved cognitive performance was also observed. Taken together, our findings supported the beneficial effects of NG on AD through adrenergic-related mechanisms and highlighted the therapeutic potential of α1-adrenergic vasomodulators against AD pathologies.

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将阻断α1肾上腺素能受体作为治疗阿尔茨海默病的新靶点

虽然淀粉样蛋白病和牛磺酸病已被认为是阿尔茨海默病（AD）大脑的特征，但最近越来越多的证据表明，脑血管变化在阿尔茨海默病的发病和发展过程中起着病理作用。在疾病的早期阶段恢复或改善受损的脑血管功能可能会对缓解阿尔茨海默病的认知功能衰退有益。在本研究中，我们评估了尼麦角林（NG，一种著名的α1肾上腺素能受体（ADR）阻断剂和血管扩张剂）通过改善血管异常对AD的潜在治疗效果。我们的体外研究数据显示，在α1-ADR过量表达的N2a细胞中，NG可以逆转β-淀粉样蛋白1-42（Aβ1-42）诱导的PKC/ERK1/2激活，这是α1-ADR激活的下游途径。NG 还能阻断 Aβ1-42- 或苯肾上腺素诱导的离体大鼠动脉收缩。所有这些体外数据可能表明，Aβ对血管功能的影响依赖于ADR，而NG具有逆转作用。此外，还在 PSAPP 转基因 AD 小鼠模型中研究了 NG 治疗对脑血管收缩、血管重塑和认知能力下降的改善作用。与体外研究结果一致，长期服用 NG 能明显改善脑血管功能障碍和脑内 Aβ 斑块沉积。此外，还观察到认知能力有所改善。综上所述，我们的研究结果支持伍格通过肾上腺素能相关机制对注意力缺失症产生有益影响，并强调了α1-肾上腺素能血管调节剂对注意力缺失症病理的治疗潜力。

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来源期刊

ACS Applied Energy Materials Materials Science-Materials Chemistry

CiteScore

10.30

自引率

6.20%

发文量

1368

期刊介绍： ACS Applied Energy Materials is an interdisciplinary journal publishing original research covering all aspects of materials, engineering, chemistry, physics and biology relevant to energy conversion and storage. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important energy applications.