Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Acta Pharmacol Sin. 2022 Aug;43(8):1916-1927. doi: 10.1038/s41401-021-00810-5. Epub 2021 Dec 10.
PTEN-induced putative kinase 1 (PINK1)/parkin pathway mediates mitophagy, which is a specialized form of autophagy. Evidence shows that PINK1 can exert protective effects against stress-induced neuronal cell death. In the present study we investigated the effects of PINK1 overexpression on tau hyperphosphorylation, mitochondrial dysfunction and oxidative stress in a specific rat model of tau hyperphosphorylation. We showed that intracerebroventricular (ICV) microinjection of forskolin (FSK, 80 μmol) induced tau hyperphosphorylation in the rat brain and resulted in significant spatial working memory impairments in Y-maze test, accompanied by synaptic dysfunction (reduced expression of synaptic proteins synaptophysin and postsynaptic density protein 95), and neuronal loss in the hippocampus. Adeno-associated virus (AAV)-mediated overexpression of PINK1 prevented ICV-FSK-induced cognition defect and pathological alterations in the hippocampus, whereas PINK1-knockout significantly exacerbated ICV-FSK-induced deteriorated effects. Furthermore, we revealed that AAV-PINK1-mediated overexpression of PINK1 alleviated ICV-FSK-induced tau hyperphosphorylation by restoring the activity of PI3K/Akt/GSK3β signaling. PINK1 overexpression reversed the abnormal changes in mitochondrial dynamics, defective mitophagy, and decreased ATP levels in the hippocampus. Moreover, PINK1 overexpression activated Nrf2 signaling, thereby increasing the expression of antioxidant proteins and reducing oxidative damage. These results suggest that PINK1 deficiency exacerbates FSK-induced tau pathology, synaptic damage, mitochondrial dysfunction, and antioxidant system defects, which were reversed by PINK1 overexpression. Our data support a critical role of PINK1-mediated mitophagy in controlling mitochondrial quality, tau hyperphosphorylation, and oxidative stress in a rat model of Alzheimer's disease.
PTEN 诱导的假定激酶 1（PINK1）/parkin 通路介导自噬，这是自噬的一种特殊形式。有证据表明，PINK1 可以发挥对应激诱导的神经元细胞死亡的保护作用。在本研究中，我们研究了 PINK1 过表达对 tau 过度磷酸化、线粒体功能障碍和氧化应激的影响，在 tau 过度磷酸化的特定大鼠模型中。我们表明，脑室（ICV）内注射 forskolin（FSK，80μmol）诱导大鼠脑内 tau 过度磷酸化，并导致 Y 迷宫测试中空间工作记忆受损，伴有突触功能障碍（突触蛋白突触小体和突触后密度蛋白 95 的表达减少）和海马神经元丢失。腺相关病毒（AAV）介导的 PINK1 过表达可预防 ICV-FSK 诱导的认知缺陷和海马病理改变，而 PINK1 敲除则显著加剧了 ICV-FSK 诱导的恶化作用。此外，我们揭示 AAV-PINK1 介导的 PINK1 过表达通过恢复 PI3K/Akt/GSK3β 信号通路的活性来减轻 ICV-FSK 诱导的 tau 过度磷酸化。PINK1 过表达逆转了海马中异常的线粒体动力学变化、有缺陷的线粒体自噬以及 ATP 水平的降低。此外，PINK1 过表达激活了 Nrf2 信号通路，从而增加了抗氧化蛋白的表达并减少了氧化损伤。这些结果表明，PINK1 缺乏加剧了 FSK 诱导的 tau 病理学、突触损伤、线粒体功能障碍和抗氧化系统缺陷，这些缺陷被 PINK1 过表达所逆转。我们的数据支持 PINK1 介导的线粒体自噬在控制阿尔茨海默病大鼠模型中线粒体质量、tau 过度磷酸化和氧化应激中的关键作用。
