USF Health Byrd Alzheimer's Institute, Department of Molecular of Medicine, University of South Florida, Morsani College of Medicine, Tampa, FL, 33613, USA.
James A. Haley Veteran's Administration Hospital, Tampa, FL, 33612, USA.
Sci Rep. 2017 Sep 14;7(1):11532. doi: 10.1038/s41598-017-09996-3.
Amyloid β (Aβ) accumulation is an early event in the pathogenesis of Alzheimer's disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Aβ deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Aβ-induced mitochondrial and synaptic dysfunction. In this study, we show that activated cofilin (S3A) preferentially forms a complex with p53 and promotes its mitochondrial and nuclear localization, resulting in transcription of p53-responsive genes and promotion of apoptosis. Conversely, reduction of endogenous cofilin by knockdown or genetic deficiency inhibits mitochondrial and nuclear translocation of p53 in cultured cells and in APP/PS1 mice. This cofilin-p53 pro-apoptotic pathway is subject to negative regulation by PLD1 thorough cofilin inactivation and inhibition of cofilin/p53 complex formation. Finally, activated cofilin is unable to induce apoptosis in cells genetically lacking p53. These findings taken together indicate that cofilin coopts and requires the nuclear and mitochondrial pro-apoptotic p53 program to induce and execute apoptosis, while PLD1 functions in a regulatory multi-brake capacity in this pathway.
淀粉样蛋白 β（Aβ）的积累是阿尔茨海默病（AD）发病机制中的早期事件，导致线粒体和突触功能障碍、tau 积累以及最终神经元死亡。虽然 p53 凋亡途径显然与 Aβ 沉积和神经元凋亡有关，但导致 AD 中 p53 激活的关键上游因素尚不清楚。我们之前已经表明，丝切蛋白（cofilin）的激活在 Aβ 诱导的线粒体和突触功能障碍中起着关键作用。在这项研究中，我们表明激活的丝切蛋白（S3A）优先与 p53 形成复合物，并促进其在线粒体和核内的定位，导致 p53 反应基因的转录和促进细胞凋亡。相反，在培养的细胞和 APP/PS1 小鼠中，通过敲低或基因缺失减少内源性丝切蛋白会抑制 p53 的线粒体和核内易位。这种丝切蛋白-p53 促凋亡途径受到 PLD1 的负调控，通过丝切蛋白失活和抑制丝切蛋白/p53 复合物的形成来抑制。最后，在遗传上缺乏 p53 的细胞中，激活的丝切蛋白无法诱导细胞凋亡。这些发现表明，丝切蛋白协同并需要核和线粒体促凋亡的 p53 程序来诱导和执行凋亡，而 PLD1 在该途径中发挥调节多制动的作用。
