Wang Hoau-Yan, Pei Zhe, Lee Kuo-Chieh, Nikolov Boris, Doehner Tamara, Puente John, Friedmann Nadav, Burns Lindsay H
Department of Molecular, Cellular and Biomedical Sciences, City University of New York School of Medicine, New York, NY, United States.
Department of Biology and Neuroscience, Graduate School of the City University of New York, New York, NY, United States.
Front Aging. 2023 Jun 29;4:1175601. doi: 10.3389/fragi.2023.1175601. eCollection 2023.
Implicated in both aging and Alzheimer's disease (AD), mammalian target of rapamycin (mTOR) is overactive in AD brain and lymphocytes. Stimulated by growth factors such as insulin, mTOR monitors cell health and nutrient needs. A small molecule oral drug candidate for AD, simufilam targets an altered conformation of the scaffolding protein filamin A (FLNA) found in AD brain and lymphocytes that induces aberrant FLNA interactions leading to AD neuropathology. Simufilam restores FLNA's normal shape to disrupt its AD-associated protein interactions. We measured mTOR and its response to insulin in lymphocytes of AD patients before and after oral simufilam compared to healthy control lymphocytes. mTOR was overactive and its response to insulin reduced in lymphocytes from AD versus healthy control subjects, illustrating another aspect of insulin resistance in AD. After oral simufilam, lymphocytes showed normalized basal mTOR activity and improved insulin-evoked mTOR activation in mTOR complex 1, complex 2, and upstream and downstream signaling components (Akt, p70S6K and phosphorylated Rictor). Suggesting mechanism, we showed that FLNA interacts with the insulin receptor until dissociation by insulin, but this linkage was elevated and its dissociation impaired in AD lymphocytes. Simufilam improved the insulin-mediated dissociation. Additionally, FLNA's interaction with Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN), a negative regulator of mTOR, was reduced in AD lymphocytes and improved by simufilam. Reducing mTOR's basal overactivity and its resistance to insulin represents another mechanism of simufilam to counteract aging and AD pathology. Simufilam is currently in Phase 3 clinical trials for AD dementia.
雷帕霉素哺乳动物靶蛋白（mTOR）与衰老和阿尔茨海默病（AD）均有关联，在AD患者的大脑和淋巴细胞中过度活跃。mTOR受胰岛素等生长因子刺激，监测细胞健康状况和营养需求。Simufilam是一种用于治疗AD的小分子口服候选药物，其作用靶点是在AD患者大脑和淋巴细胞中发现的支架蛋白细丝蛋白A（FLNA）的构象改变，这种改变会诱导异常的FLNA相互作用，导致AD神经病理学变化。Simufilam可恢复FLNA的正常形状，以破坏其与AD相关的蛋白质相互作用。我们比较了AD患者口服simufilam前后淋巴细胞中mTOR及其对胰岛素的反应，以及健康对照淋巴细胞。与健康对照受试者相比，AD患者淋巴细胞中的mTOR过度活跃，且对胰岛素的反应降低，这说明了AD中胰岛素抵抗的另一个方面。口服simufilam后，淋巴细胞的基础mTOR活性恢复正常，mTOR复合物1、复合物2以及上游和下游信号成分（Akt、p70S6K和磷酸化的Rictor）的胰岛素诱发的mTOR激活得到改善。为了阐明作用机制，我们发现FLNA与胰岛素受体相互作用，直至被胰岛素解离，但在AD淋巴细胞中这种联系增强，其解离受损。Simufilam改善了胰岛素介导的解离。此外，在AD淋巴细胞中，FLNA与mTOR的负调节因子10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）的相互作用减少，而simufilam可改善这种相互作用。降低mTOR的基础过度活性及其对胰岛素的抵抗是simufilam对抗衰老和AD病理的另一种机制。Simufilam目前正处于治疗AD痴呆的3期临床试验阶段。
