During Alzheimer's (AD), tau protein suffers from abnormal post-translational modifications, including cleaving by caspase-3. These tau forms affect synaptic plasticity contributing to the cognitive decline observed in the early stages of AD. In addition, caspase-3 cleaved tau (TauC3) impairs mitochondrial dynamics and organelles transport, which are both relevant processes for synapse. We recently showed that the absence of tau expression reverts age-associated cognitive and mitochondrial failure by blocking the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial complex involved in calcium regulation and apoptosis. Therefore, we studied the effects of TauC3 against the dendritic spine and synaptic vesicle formation and the possible role of mPTP in these alterations. We used mature hippocampal mice neurons to express a reporter protein (GFP, mCherry), coupled to full-length human tau protein (GFP-T4, mCherry-T4), and coupled to human tau protein cleaved at D421 by caspase-3 (GFP-T4C3, mCherry-T4C3) and synaptic elements were evaluated.

Treatment with cyclosporine A (CsA), an immunosuppressive drug with inhibitory activity on mPTP, prevented ROS increase and mitochondrial depolarization induced by TauC3 in hippocampal neurons. These results were corroborated with immortalized cortical neurons in which ROS increase and ATP loss induced by this tau form were prevented by CsA. Interestingly, TauC3 expression significantly reduced dendritic spine density (filopodia type) and synaptic vesicle number in hippocampal neurons. Also, neurons transfected with TauC3 showed a significant accumulation of synaptophysin protein in their soma. More importantly, all these synaptic alterations were prevented by CsA, suggesting an mPTP role in these negative changes derived from TauC3 expression.

在阿尔茨海默氏症 (AD) 期间，tau 蛋白会遭受异常的翻译后修饰，包括被 caspase-3 切割。这些 tau 形式影响突触可塑性，导致在 AD 的早期阶段观察到的认知能力下降。此外，caspase-3 cleaved tau (TauC3) 会损害线粒体动力学和细胞器运输，这两个过程都是突触的相关过程。我们最近表明，tau 表达的缺失通过阻断线粒体通透性转换孔 (mPTP) 来恢复与年龄相关的认知和线粒体衰竭。mPTP 是参与钙调节和细胞凋亡的线粒体复合物。因此，我们研究了 TauC3 对树突棘和突触小泡形成的影响以及 mPTP 在这些改变中的可能作用。

用对 mPTP 具有抑制活性的免疫抑制药物环孢菌素 A (CsA) 进行治疗可防止海马神经元中 TauC3 诱导的 ROS 增加和线粒体去极化。这些结果得到永生化皮层神经元的证实，其中 ROS 增加和由这种 tau 形式诱导的 ATP 损失被 CsA 阻止。有趣的是，TauC3 表达显着降低了海马神经元中的树突棘密度（丝状伪足类型）和突触小泡数量。此外，用 TauC3 转染的神经元在其胞体中显示出显着的突触素蛋白积累。更重要的是，所有这些突触改变都被 CsA 阻止，表明 mPTP 在这些源自 TauC3 表达的负面变化中发挥作用。