Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2-/- Mouse Model of Sporadic Alzheimer's Disease.
Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2-/- Mouse Model of Sporadic Alzheimer's Disease.
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DOI：
10.3233/jad-200617
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Thibault O
中科院分区：
文献类型：
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作者：
Ghoweri AO;Gagolewicz P;Frazier HN;Gant JC;Andrew RD;Bennett BM;Thibault O
神经元和星形胶质细胞中的信号传导失调参与了阿尔茨海默病大脑中的病理生理改变，包括淀粉样蛋白-β、过度磷酸化 tau 蛋白的增加、炎症、钙失调和氧化应激。这些通常在行为、认知和非认知缺陷出现之前就被注意到。然而，这些病理变化在多大程度上共同或独立发挥作用尚不清楚。人们对钙失调和氧化应激之间的时间关系知之甚少，因为一些报告表明钙失调会促进活性氧的形成增加，而另一些报告则支持相反的观点。先前的工作已经量化了与乙醛脱氢酶 2 敲除 (Aldh2–/–) 小鼠（一种散发性阿尔茨海默病的非转基因模型）氧化应激相关的几个关键结果指标。在这里，我们通过使用电生理学和成像方法测量钙依赖性过程，并重点关注 Aldh2–/– 小鼠的后超极化 (AHP)、突触激活、体细胞钙和长时程增强，测试了早期氧化应激可以促进整个衰老过程中钙失调的假设。我们的结果表明，在 Aldh2–/– 动物中，AHP 与年龄相关的显着下降，同时 AHP 缓慢幅度增加。尽管与野生型相比，Aldh2-/- 动物的长期增强维持显着降低，但突触兴奋性的测量没有改变。由于动物模型中钙和钙依赖性过程的变化很少，且显示 HNE 加合物、Aβ、β-tau 和活化的半胱天冬酶随年龄增长而显着增加，因此目前的研究结果并不支持神经元钙失调与不受控制的氧化应激之间的直接联系。
Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer’s disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear. Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures associated with oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2–/–) mice, a non-transgenic model of sporadic Alzheimer’s disease. Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2–/– mouse. Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2–/– animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2–/– animals compared to wild-type. With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aβ, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress.