Heller Lawrence I, Lowe Allison S, Del Rosario Hernández Thaís, Gore Sayali V, Chatterjee Mallika, Creton Robbert
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
Amity Institute of Neuropsychology and Neurosciences, Amity University, Noida 201303, India.
J Dement Alzheimers Dis. 2025 Jun;2(2). doi: 10.3390/jdad2020010. Epub 2025 May 1.
BACKGROUND/OBJECTIVE: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer's disease.
Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin.
Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin-NFAT pathway, like cyclo-sporine A, providing a potential mechanism.
Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer's disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration.
背景/目的：环孢素A及其他钙调神经磷酸酶抑制剂已被确定为预防阿尔茨海默病的潜在治疗方法。我们之前发现，钙调神经磷酸酶抑制剂在斑马鱼幼体中引发独特的行为特征，表现为活动增加、听觉过敏和视觉引导行为减少。使用Z-LaP Tracker筛选大量FDA批准的化合物库发现，一些心脏药物产生类似的行为特征，表明这些药物可能发挥与预防或改善阿尔茨海默病相关的钙调神经磷酸酶抑制剂样作用。
使用神经网络模型Z-LaP Tracker筛选大量FDA批准的药物库，发现一组65种药物表现出环孢素A样的行为特征。其中14种药物为心脏药物，包括血管紧张素受体阻滞剂、β受体阻滞剂、α肾上腺素能受体拮抗剂和一种他汀类药物。
在Z-LaP Tracker中，将这些心脏药物与环孢素A联合给药显示出协同作用：与单独使用较高剂量的每种药物相比，较低剂量的每种心脏药物与较低剂量的环孢素A联合使用可产生相似或更大的行为效应。其他研究表明，这些心脏药物中的许多药物直接或间接抑制钙调神经磷酸酶-NFAT途径，与环孢素A类似，这提供了一种潜在机制。
低剂量环孢素A与特定心脏药物联合给药可能是预防阿尔茨海默病发生并同时治疗心血管功能障碍的潜在有效治疗策略，同时减轻与高剂量环孢素A相关的副作用。鉴于许多患者中心脏病先于阿尔茨海默病出现，医生或许能够制定出针对这两种病症的治疗方案。我们的结果表明，钙调神经磷酸酶抑制剂与辛伐他汀、厄贝沙坦、西洛他唑、多沙唑嗪或奈必洛尔联合使用是未来探索最有前景的候选方案。
