Motor coordination and synaptic plasticity deficits are associated with increased cerebellar activity of NADPH oxidase, CAMKII, and PKC at preplaque stage in the TgCRND8 mouse model of Alzheimer's disease
Motor coordination and synaptic plasticity deficits are associated with increased cerebellar activity of NADPH oxidase, CAMKII, and PKC at preplaque stage in the TgCRND8 mouse model of Alzheimer's disease
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DOI：
10.1016/j.neurobiolaging.2018.02.025
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发表时间：
2018-08-01
影响因子：
4.2
通讯作者：
Miniaci, Maria Concetta
中科院分区：
文献类型：
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作者：
Russo, Roberto;Cattaneo, Fabio;Miniaci, Maria Concetta
大量研究表明，小脑在阿尔茨海默病中经历结构和功能性神经退行性变化。本研究的目的是通过行为、电生理学和分子分析来检查 TgCRND8 小鼠病理学早期斑块前阶段小脑的改变程度。平衡木测试和足迹分析显示，与同窝小鼠相比，2 个月大的 TgCRND8 小鼠存在显着的运动协调和平衡缺陷。对转基因小鼠小脑切片进行的膜片钳记录显示突触可塑性缺陷和平行纤维浦肯野细胞突触去甲肾上腺素能调节的丧失，表明由于淀粉样前体蛋白过度表达而导致小脑回路的早期功能障碍。最后，蛋白质印迹分析显示，2 个月大的转基因小鼠小脑中烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶亚基 p47(phox) 和 p67(phox) 以及 Ca2+/钙调蛋白依赖性蛋白激酶和蛋白激酶 C α 的表达增强。因此，我们提出甲酰基肽受体2-活性氧-Ca2+/钙调蛋白依赖性蛋白激酶II-蛋白激酶Cα通路存在自我维持的反馈环路，该通路可能促进阿尔茨海默病早期活性氧的产生，最终导致病理表型的恶化。 (C) 2018 Elsevier Inc. 保留所有权利。
Numerous studies indicate that the cerebellum undergoes structural and functional neurodegenerative changes in Alzheimer's disease. The purpose of this study was to examine the extent of cerebellar alterations at early, preplaque stage of the pathology in TgCRND8 mice through behavioral, electrophysiological, and molecular analysis. Balance beam test and foot-printing analysis revealed significant motor coordination and balance deficits in 2-month-old TgCRND8 mice compared to their littermates. Patch-clamp recordings performed on cerebellar slices of transgenic mice showed synaptic plasticity deficit and loss of noradrenergic modulation at parallel fiber-Purkinje cell synapse suggesting an early dysfunction of the cerebellar circuitry due to amyloid precursor protein overexpression. Finally, western blot analysis revealed an enhanced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47(phox) and p67(phox) as well as Ca2+/calmodulin-dependent protein kinase and protein kinase C alpha in the cerebellum of 2-month-old transgenic mice. Therefore, we propose the existence of self-sustaining feedback loop involving the formyl peptide receptor 2-reactive oxygen species-Ca2+/calmodulin-dependent protein kinase II-protein kinase C alpha pathway that may promote reactive oxygen species generation in the early stage of Alzheimer's disease and eventually contribute to the exacerbation of pathological phenotype. (C) 2018 Elsevier Inc. All rights reserved.