Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimers disease neurons: implications for mitochondrial dysfunction and neuronal damage
Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimers disease neurons: implications for mitochondrial dysfunction and neuronal damage
复制标题
DOI：
10.1093/hmg/dds072
复制
发表时间：
2012-06-01
影响因子：
3.5
通讯作者：
Reddy, P. Hemachandra
中科院分区：
文献类型：
--
作者：
Manczak, Maria;Reddy, P. Hemachandra
我们最近报道了受 AD 影响的神经元中线粒体分裂增加和融合减少、β 淀粉样蛋白 (A) 与线粒体分裂蛋白 Drp1 相互作用增加、线粒体碎片增加、线粒体轴突运输受损和突触变性。在本研究中，我们扩展了之前的研究，以确定磷酸化 tau 是否与 Drp1 相互作用，并阐明 AD 进展中的线粒体损伤。我们还研究了 AD 患者死后脑组织以及 APP、APP/PS1 和 3XTg.AD 小鼠脑组织中的 GTP 酶活性，这对线粒体断裂至关重要。通过免疫共沉淀和免疫荧光分析，我们首次证明了磷酸化 tau 和 Drp1 之间的物理相互作用。 AD 患者死后额叶皮层组织以及 APP、APP/PS1 和 3XTg.AD 小鼠的皮层组织中线粒体裂变连接的 GTPase 活性显着升高。基于这些发现，我们得出结论，Drp1 与 A 和磷酸化 tau 相互作用，可能导致线粒体过度断裂以及线粒体和突触缺陷，最终可能导致神经元损伤和认知能力下降。旨在减少 Drp1、A 和/或磷酸化 tau 表达的治疗可能会减少 Drp1 与磷酸化 tau 之间的相互作用以及 Drp1 与 A 之间的相互作用，从而保护神经元免受过量 Drp1、A 和/或磷酸化 tau 的毒性损伤。
We recently reported increased mitochondrial fission and decreased fusion, increased amyloid beta (A) interaction with the mitochondrial fission protein Drp1, increased mitochondrial fragmentation, impaired axonal transport of mitochondria and synaptic degeneration in neurons affected by AD. In the present study, we extended our previous investigations to determine whether phosphorylated tau interacts with Drp1 and to elucidate mitochondrial damage in the progression of AD. We also investigated GTPase activity, which is critical for mitochondrial fragmentation, in postmortem brain tissues from patients with AD and brain tissues from APP, APP/PS1 and 3XTg.AD mice. Using co-immunoprecipitation and immunofluorescence analyses, for the first time, we demonstrated the physical interaction between phosphorylated tau and Drp1. Mitochondrial fission-linked GTPase activity was significantly elevated in the postmortem frontal cortex tissues from AD patients and cortical tissues from APP, APP/PS1 and 3XTg.AD mice. On the basis of these findings, we conclude that Drp1 interacts with A and phosphorylated tau, likely leading to excessive mitochondrial fragmentation, and mitochondrial and synaptic deficiencies, ultimately possibly leading to neuronal damage and cognitive decline. Treatment designed to reduce the expression of Drp1, A and/or phosphorylated tau may decrease the interaction between Drp1 and phosphorylated tau and the interaction between Drp1 and A, conferring protection to neurons from toxic insults of excessive Drp1, A and/or phosphorylated tau.