Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice.
Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice.
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DOI：
10.3233/jad-201015
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Trushina E
中科院分区：
文献类型：
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作者：
Stojakovic A;Chang SY;Nesbitt J;Pichurin NP;Ostroot MA;Aikawa T;Kanekiyo T;Trushina E
过度磷酸化的tau （pTau）蛋白的积累与阿尔茨海默病（AD）的突触功能障碍有关。我们之前已经证明，家族性AD小鼠模型中的神经保护可以通过靶向线粒体复合体I （MCI）和激活适应性应激反应来实现。该策略对ptau相关病理的疗效尚不清楚。目的：探讨特异性MCI抑制剂三环吡酮化合物CP2对18月龄3xTg-AD小鼠pTau水平、记忆功能、长时程增强（LTP）和能量稳态的影响，并探讨其潜在机制。CP2分别给予3.5 ~ 18月龄的雄性和雌性3xTg-AD小鼠。采用Morris水迷宫评估认知功能。外周用葡萄糖耐量试验测量葡萄糖代谢，脑用氟脱氧葡萄糖F18正电子发射断层扫描（FDG-PET）测量葡萄糖代谢。用海马电生理学评估LTP。western blotting检测与神经保护机制相关的关键蛋白的表达。慢性CP2治疗可恢复3xTg-AD雌性小鼠的突触活性；雌雄3xTg-AD小鼠的认知功能、突触蛋白水平、葡萄糖代谢和能量稳态均得到改善。人脑中pTau蛋白的显著减少与2A型蛋白磷酸酶（PP2A）活性的增加以及细胞周期蛋白依赖性激酶5 （CDK5）和糖原合成酶激酶3β (GSK3β)活性的降低有关。CP2治疗可以防止症状性3xTg-AD小鼠的突触功能障碍和记忆障碍，并降低人类pTau水平，表明用小分子特异性MCI抑制剂靶向线粒体是治疗AD的一种有希望的策略。
Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer’s disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. CP2 was administered to male and female 3xTg-AD mice from 3.5–18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β). CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.