Synapsin-Promoted Caveolin-1 Overexpression Maintains Mitochondrial Morphology and Function in PSAPP Alzheimer's Disease Mice.
Synapsin-Promoted Caveolin-1 Overexpression Maintains Mitochondrial Morphology and Function in PSAPP Alzheimer's Disease Mice.
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突触蛋白促进的小窝蛋白-1过表达维持PSAPP阿尔茨海默病小鼠的线粒体形态和功能。
DOI：
10.3390/cells10092487
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发表时间：
2021-09-20
期刊：
影响因子：
6
通讯作者：
Head BP
中科院分区：
文献类型：
--
作者：
Wang S;Ichinomiya T;Terada Y;Wang D;Patel HH;Head BP
线粒体功能障碍在阿尔茨海默病（AD）的病理学中起着关键作用。破坏线粒体动力学（即，融合/裂变平衡），这是正常线粒体结构和功能所必需的，在AD中有记载。Caveolin-1（Cav-1）是一种膜/脂筏（MLR）支架蛋白，调节几种不同细胞类型如肝细胞和癌细胞中的代谢途径。先前，我们已经显示了9个月（m）大的PSAPP小鼠海马中Cav-1的表达降低，而使用突触蛋白启动子的神经元靶向Cav-1的海马过表达（即，SynCav 1）在9和12 m PSAPP小鼠中保留了认知功能、神经元形态和突触超微结构。考虑到能量产生在维持正常神经元和突触功能和存活中的核心作用，本研究揭示PSAPP小鼠表现出线粒体分布、形态和呼吸紊乱。相反，SynCav 1减轻线粒体损伤和损失，并增强线粒体呼吸。此外，通过检查线粒体动力学，我们发现PSAPP小鼠表现出线粒体动力蛋白相关的GT3蛋白（DRP 1）磷酸化的显着增加，导致过度的线粒体碎片化和功能障碍。相比之下，海马传递SynCav 1显着降低p-DRP 1和增加的线粒体融合蛋白，线粒体融合蛋白1（Mfn 1）在PSAPP小鼠，分子事件，这可能是机械解释的线粒体分裂/融合和代谢弹性的平衡保存在12 m PSAPP-SynCav 1小鼠。我们的数据表明，Cav-1在维持正常的线粒体形态和功能，通过影响线粒体动力学的关键作用，并解释了一个分子和细胞机制的基础上，先前报道的神经保护和认知保护诱导SynCav 1在PSAPP小鼠模型的AD。
Mitochondrial dysfunction plays a pivotal role in the Alzheimer’s Disease (AD) pathology. Disrupted mitochondrial dynamics (i.e., fusion/fission balance), which are essential for normal mitochondria structure and function, are documented in AD. Caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein regulates metabolic pathways in several different cell types such as hepatocytes and cancer cells. Previously, we have shown decreased expression of Cav-1 in the hippocampus of 9-month (m) old PSAPP mice, while hippocampal overexpression of neuron-targeted Cav-1 using the synapsin promoter (i.e., SynCav1) preserved cognitive function, neuronal morphology, and synaptic ultrastructure in 9 and 12 m PSAPP mice. Considering the central role of energy production in maintaining normal neuronal and synaptic function and survival, the present study reveals that PSAPP mice exhibit disrupted mitochondrial distribution, morphometry, and respiration. In contrast, SynCav1 mitigates mitochondrial damage and loss and enhances mitochondrial respiration. Furthermore, by examining mitochondrial dynamics, we found that PSAPP mice showed a significant increase in the phosphorylation of mitochondrial dynamin-related GTPase protein (DRP1), resulting in excessive mitochondria fragmentation and dysfunction. In contrast, hippocampal delivery of SynCav1 significantly decreased p-DRP1 and augmented the level of the mitochondrial fusion protein, mitofusin1 (Mfn1) in PSAPP mice, a molecular event, which may mechanistically explain for the preserved balance of mitochondria fission/fusion and metabolic resilience in 12 m PSAPP-SynCav1 mice. Our data demonstrate the critical role for Cav-1 in maintaining normal mitochondrial morphology and function through affecting mitochondrial dynamics and explain a molecular and cellular mechanism underlying the previously reported neuroprotective and cognitive preservation induced by SynCav1 in PSAPP mouse model of AD.
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影响因子：
9
作者：
Han, Mei;Pioronska, Weronika;Meyer, Christoph
通讯作者：
Meyer, Christoph
影响因子：
10.6
作者：
Mandyam CD;Schilling JM;Cui W;Egawa J;Niesman IR;Kellerhals SE;Staples MC;Busija AR;Risbrough VB;Posadas E;Grogman GC;Chang JW;Roth DM;Patel PM;Patel HH;Head BP
通讯作者：
Head BP
影响因子：
6
作者：
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通讯作者：
Ankarcrona M
影响因子：
3.5
作者：
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通讯作者：
Reddy, P. Hemachandra
影响因子：
11.4
作者：
Cummins, Nadia;Tweedie, Andrea;Goetz, Juergen
通讯作者：
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