Ample studies indicate that calcineurin, a Ca²⁺/calmodulin-sensitive phosphatase, plays a key role in the initiation and/or clinical progression of Alzheimer's disease, and alteration of calcineurin has been confirmed in Alzheimer’s disease brain, impacting tau proteins and amyloid beta (Aβ) levels and resulting in neuronal cell death. As, it is sensible to deliberate the likelihood of calcineurin inhibition as a pharmacological target in the progress of novel Alzheimer’s disease therapies, we investigated the neuroprotective efficacy of dimethyl fumarate (DMF) via calcineurin dependent downstream targets in oligomeric Aβ_1-42 treated neuroblastoma SH-SY5Y cells. DMF pre-treatment reduced LDH release, increased cell survival and decreased calcineurin activity in Aβ_1-42-incubated cells. DMF was found to block calcineurin dependent apoptosis induced by Aβ_1-42 through Bcl-2 linked death protein (BAD) and cAMP response element binding (CREB) dephosphorylation; moreover, rescued the opposing effect of Aβ_1-42 on CREB-driven transcription in cells transfected with the CRE-SEAP reporter gene indicating its efficacy on long term potentiation and synaptic plasticity. DMF reversed Aβ_1-42-induced enhancement in the active form of nuclear factor of activated T-cells (NFAT1) and further associated beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) expression, BACE1 promoter activity and BACE1 enzymatic activity. DMF exhibited another neuroprotective mechanism against Aβ_1-42 treatment by reducing nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) dependent BACE1 gene transcription. DMF does not alter either beta amyloid precursor protein (βAPP) or its mRNA levels in SH-SY5Y cells, confirming that it does not possess amyloidogenic effect. Inhibiting molecular events related to Aβ_1-42-induced calcineurin activity by DMF, may be an approach towards finding suitable treatment for Alzheimer’s disease.

大量研究表明，钙调神经磷酸酶是一种 Ca ²⁺ /钙调蛋白敏感的磷酸酶，在阿尔茨海默病的发生和/或临床进展中起着关键作用，并且已经证实在阿尔茨海默病大脑中钙调神经磷酸酶的改变会影响 tau 蛋白和淀粉样蛋白β (Aβ) 水平并导致神经元细胞死亡。由于在新型阿尔茨海默病疗法的进展中考虑钙调神经磷酸酶抑制作为药理学靶标的可能性是明智的，我们通过寡聚_{Aβ1-42 中}钙调神经磷酸酶依赖性下游靶标研究了富马酸二甲酯 (DMF) 的神经保护功效处理的神经母细胞瘤 SH-SY5Y 细胞。DMF 预处理减少了 LDH 释放，增加了细胞存活率并降低了 Aβ _1-42孵育细胞中的钙调神经磷酸酶活性。发现 DMF通过 Bcl-2 连接的死亡蛋白 (BAD) 和 cAMP 反应元件结合 (CREB) 去磷酸化阻断由 Aβ _1-42诱导的钙调神经磷酸酶依赖性细胞凋亡；此外，在用 CRE-SEAP 报告基因转染的细胞中挽救了 Aβ _1-42对 CREB ​​驱动转录的相反作用，表明其对长期增强和突触可塑性的功效。DMF 逆转 Aβ _1-42- 诱导活化 T 细胞 (NFAT1) 核因子活性形式的增强，并进一步关联 β 位点淀粉样前体蛋白裂解酶-1 (BACE1) 表达、BACE1 启动子活性和 BACE1 酶活性。DMF通过减少活化 B 细胞 (NFκB) 依赖的 BACE1 基因转录的核因子κ-轻链增强子，表现出另一种针对 Aβ _1-42治疗的神经保护机制。DMF 不会改变 SH-SY5Y 细胞中的 β 淀粉样前体蛋白 (βAPP) 或其 mRNA 水平，证实它不具有淀粉样蛋白生成作用。通过 DMF抑制与 Aβ _1-42诱导的钙调神经磷酸酶活性相关的分子事件，可能是寻找阿尔茨海默病合适治疗方法的一种方法。