Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Regional de Málaga, UGC Salud Mental, Málaga, Spain.
Facultad de Ciencias, Universidad de Málaga, Málaga, Spain.
Br J Pharmacol. 2022 Oct;179(19):4655-4672. doi: 10.1111/bph.15907. Epub 2022 Jul 18.
Recent evidence links brain insulin resistance with neurodegenerative diseases, where hyperphosphorylated tau protein contributes to neuronal cell death. In the present study, we aimed to evaluate if d-pinitol inositol, which acts as an insulin sensitizer, affects the phosphorylation status of tau protein.
We studied the pharmacological effect of d-pinitol on insulin signalling and tau phosphorylation in the hippocampus of Wistar and Zucker rats. To this end, we evaluated by western blotting the Akt pathway and its downstream proteins as being one of the main insulin-mediator pathways. Also, we explored the functional status of additional kinases phosphorylating tau, including PKA, ERK1/2, AMPK and CDK5. We utilized the 3xTg mouse model as a control for tauopathy, since it carries tau mutations that promote phosphorylation and aggregation.
Surprisingly, we discovered that oral d-pinitol treatment lowered tau phosphorylation significantly, but not through the expected kinase GSK-3 regulation. An extensive search for additional kinases phosphorylating tau revealed that this effect was mediated through a mechanism dependent on the reduction of the activity of the CDK5, affecting both its p35 and p25 subunits. This effect disappeared in leptin-deficient Zucker rats, uncovering that the association of leptin deficiency, obesity, dyslipidaemia and hyperinsulinaemia abrogates d-pinitol actions on tau phosphorylation. The 3xTg mice confirmed d-pinitol effectiveness in a genetic AD-tauopathy.
The present findings suggest that d-pinitol, by regulating CDK5 activity through a decrease of CDK5R1, is a potential drug for developing treatments for neurological disorders such as tauopathies.
最近的证据表明，大脑胰岛素抵抗与神经退行性疾病有关，其中过度磷酸化的 tau 蛋白导致神经元细胞死亡。在本研究中，我们旨在评估作为胰岛素增敏剂的 D-松醇是否会影响 tau 蛋白的磷酸化状态。
我们研究了 D-松醇对 Wistar 和 Zucker 大鼠海马胰岛素信号和 tau 磷酸化的药理作用。为此，我们通过 Western blot 评估了 Akt 途径及其下游蛋白作为主要的胰岛素介导途径之一。此外，我们还研究了磷酸化 tau 的其他激酶的功能状态，包括 PKA、ERK1/2、AMPK 和 CDK5。我们利用 3xTg 小鼠模型作为 tau 病的对照，因为它携带促进磷酸化和聚集的 tau 突变。
令人惊讶的是，我们发现口服 D-松醇治疗可显著降低 tau 磷酸化，但不是通过预期的 GSK-3 调节。对额外的 tau 磷酸化激酶进行广泛搜索发现，这种作用是通过一种依赖于 CDK5 活性降低的机制介导的，影响其 p35 和 p25 亚基。这种作用在瘦素缺乏的 Zucker 大鼠中消失，揭示了瘦素缺乏、肥胖、血脂异常和高胰岛素血症的联合作用会消除 D-松醇对 tau 磷酸化的作用。3xTg 小鼠证实了 D-松醇在遗传性 AD-tau 病中的有效性。
本研究结果表明，D-松醇通过降低 CDK5R1 来调节 CDK5 活性，是一种治疗 tau 病等神经退行性疾病的潜在药物。
