Alzheimer's Disease (AD) and Type 2 Diabetes (T2D) share a common hallmark of insulin resistance. Reportedly, two non-canonical Receptor Tyrosine Kinases (RTKs), ALK and RYK, both targets of the same micro RNA miR-1271, exhibit significant and consistent functional down-regulation in post-mortem AD and T2D tissues. Incidentally, both have Grb2 as a common downstream adapter and NOX4 as a common ROS producing factor. Here we show that Grb2 and NOX4 play critical roles in reducing the severity of both the diseases. The study demonstrates that the abundance of Grb2 in degenerative conditions, in conjunction with NOX4, reverse cytoskeletal degradation by counterbalancing the network of small GTPases. PAX4, a transcription factor for both Grb2 and NOX4, emerges as the key link between the common pathways of AD and T2D. Down-regulation of both ALK and RYK through miR-1271, elevates the PAX4 level by reducing its suppressor ARX via Wnt/β-Catenin signaling. For the first time, this study brings together RTKs beyond Insulin Receptor (IR) family, transcription factor PAX4 and both AD and T2D pathologies on a common regulatory platform.

中文翻译：

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miR-1271、PAX4 和 ALK/RYK 的关系影响阿尔茨海默病和 2 型糖尿病的细胞骨架结构

阿尔茨海默病 (AD) 和 2 型糖尿病 (T2D) 具有胰岛素抵抗的共同特征。据报道，两种非经典受体酪氨酸激酶 (RTK)，ALK 和 RYK，两者都是相同微 RNA miR-1271 的靶标，在死后 AD 和 T2D 组织中表现出显着且一致的功能下调。顺便说一下，两者都将 Grb2 作为常见的下游接头，将 NOX4 作为常见的 ROS 产生因子。在这里，我们表明 Grb2 和 NOX4 在降低这两种疾病的严重程度方面发挥着关键作用。该研究表明，退行性条件下大量的 Grb2 与 NOX4 结合，通过平衡小 GTP 酶网络来逆转细胞骨架降解。PAX4 是 Grb2 和 NOX4 的转录因子，是 AD 和 T2D 常见途径之间的关键环节。通过 miR-1271 下调 ALK 和 RYK，通过 Wnt/β-Catenin 信号传导减少其抑制因子 ARX，从而提高 PAX4 水平。这项研究首次将胰岛素受体 (IR) 家族以外的 RTK、转录因子 PAX4 以及 AD 和 T2D 病理学结合到一个共同的监管平台上。