Mitochondrial PKA Is Neuroprotective in a Cell Culture Model of Alzheimer's Disease.
Mitochondrial PKA Is Neuroprotective in a Cell Culture Model of Alzheimer's Disease.
复制标题
线粒体PKA是阿尔茨海默氏病细胞培养模型的神经保护作用。
DOI：
10.1007/s12035-021-02333-w
复制
发表时间：
2021-07
影响因子：
5.1
通讯作者：
Dagda RK
中科院分区：
文献类型：
--
作者：
Banerjee TD;Reihl K;Swain M;Torres M;Dagda RK
阿尔茨海默病（Alzheimer's disease，AD）是一种以进行性记忆丧失和认知功能下降为特征的神经退行性疾病。在海马神经元中，AD的病理特征包括细胞外淀粉样β肽（Aβ）的积聚，伴随氧化应激、线粒体功能障碍和神经元损失。神经保护性蛋白激酶A（PKA）信号转导的减少有助于AD中的线粒体片段化和神经变性。通过与蛋白质支架双特异性激活蛋白1（D-AKAP 1）结合，PKA靶向线粒体，通过磷酸化裂变调节剂动力蛋白相关蛋白1（Drp 1）促进线粒体融合。我们假设：1）内源性D-AKAP 1的内源性水平的降低有助于线粒体中PKA信号传导的降低，并且2）恢复线粒体中PKA信号传导可以逆转AD模型中神经元中的神经变性和线粒体片段化。通过免疫组织化学，我们发现内源性D-AKAP 1，而不是其他线粒体蛋白，在Aβ42肽处理的原代神经元中显著减少（10μM，24小时），以及来自无症状和有症状的AD小鼠（5X-FAD）的海马和皮质。瞬时表达野生型而非PKA结合缺陷型D-AKAP 1突变体能够减少Aβ42处理的原代神经元的线粒体分裂、树突回缩和凋亡。从机制上讲，D-AKAP 1/PKA的保护作用是通过PKA介导的Drp 1磷酸化来调节的，因为瞬时表达Drp 1的PKA磷酸化模拟突变体（Drp 1-S656 D）表型模仿D-AKAP 1减少Aβ42介导的凋亡和线粒体分裂的能力。总的来说，我们的数据表明，在AD的体外细胞培养模型中，D-AKAP 1/PKA的丢失有助于线粒体病理学和神经变性。
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive decline. In hippocampal neurons, the pathological features of AD include the accumulation of extracellular amyloid beta peptide (Aβ) accompanied by oxidative stress, mitochondrial dysfunction, and neuron loss. A decrease in neuroprotective Protein Kinase A (PKA) signaling contributes to mitochondrial fragmentation and neurodegeneration in AD. By associating with the protein scaffold Dual-Specificity Anchoring Protein 1 (D-AKAP1), PKA is targeted to the mitochondria to promote mitochondrial fusion by phosphorylating the fission modulator dynamin-related protein 1 (Drp1). We hypothesized that: 1) a decrease in the endogenous level of endogenous D-AKAP1 contributes to decreased PKA signaling in mitochondria, and that 2) restoring PKA signaling in mitochondria can reverse neurodegeneration and mitochondrial fragmentation in neurons in AD models. Through immunohistochemistry, we showed that endogenous D-AKAP1, but not other mitochondrial proteins, is significantly reduced in primary neurons treated with Aβ42 peptide (10μM, 24 hrs.), and in the hippocampus and cortex from asymptomatic and symptomatic AD mice (5X-FAD). Transiently expressing wild-type, but not a PKA-binding deficient mutant of D-AKAP1, was able to reduce mitochondrial fission, dendrite retraction, and apoptosis in primary neurons treated with Aβ42. Mechanistically, the protective effects of D-AKAP1/PKA are moderated through PKA-mediated phosphorylation of Drp1, as transiently expressing a PKA phosphomimetic mutant of Drp1 (Drp1-S656D) phenocopies D-AKAP1’s ability to reduce Aβ42-mediated apoptosis and mitochondrial fission. Overall, our data suggest that a loss of D-AKAP1/PKA contributes to mitochondrial pathology and neurodegeneration in an in vitro cell culture model of AD.
登录
查看更多内容
影响因子：
3.7
作者：
Cha MY;Han SH;Son SM;Hong HS;Choi YJ;Byun J;Mook-Jung I
通讯作者：
Mook-Jung I
DOI：
10.1016/j.bbadis.2009.07.007
发表时间：
2010-01
影响因子：
6.2
作者：
Devi, Latha;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.
影响因子：
4.1
作者：
Dagda RK;Das Banerjee T
通讯作者：
Das Banerjee T
影响因子：
3.9
作者：
Dykens, JA;Simpkins, JW;Gordon, K
通讯作者：
Gordon, K
影响因子：
4.6
作者：
Carnegie, Graeme K.;Means, Christopher K.;Scott, John D.
通讯作者：
Scott, John D.