SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer's Disease Model
SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer's Disease Model
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DOI：
10.1523/jneurosci.1446-19.2019
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发表时间：
2020-01-15
影响因子：
5.3
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
--
作者：
Cheng, Aiwu;Wang, Jing;Mattson, Mark P.
线粒体功能受损和神经元网络活动异常被认为是阿尔茨海默病（AD）发病机制的早期事件，但线粒体改变如何导致神经元回路中的异常活动尚不清楚。在这项研究中，我们研究了线粒体蛋白去乙酰化酶sirtuin 3（SIRT 3）在AD发病机制中的作用。与AppPs 1小鼠相比，Sirt 3-haploinsufficient AppPs 1小鼠（Sirt 3（+/-）AppPs 1）表现出早期癫痫样EEG活动和癫痫发作。观察到雄性和雌性Sirt 3（+/-）AppPs 1小鼠在5月龄之前过早死亡。当比较不同基因型的雄性小鼠时，Sirt 3单倍不足使大脑皮层中的GABA能中间神经元易于变性和相关的神经元网络过度兴奋。用富含酮酯的饮食喂养Sirt 3（+/-）AppPs 1 AD小鼠可增加SIRT 3表达，并防止癫痫相关死亡和GABA能神经元变性，表明Sirt 3（+/-）AppPs 1小鼠中GABA能神经元丢失加重和神经元网络过度兴奋是由SIRT 3减少引起的，并可通过SIRT 3表达增加来挽救。与AD中的保护作用一致，SIRT 3水平降低与AD患者的大脑皮质A β病理学相关。总之，SIRT 3保护GABA能中间神经元并保护脑回路免受过度兴奋，并且这种神经保护机制可以通过膳食酮酯来加强。
Impaired mitochondrial function and aberrant neuronal network activity are believed to be early events in the pathogenesis of Alzheimer's disease (AD), but how mitochondrial alterations contribute to aberrant activity in neuronal circuits is unknown. In this study, we examined the function of mitochondrial protein deacetylase sirtuin 3 (SIRT3) in the pathogenesis of AD. Compared with AppPs1 mice, Sirt3-haploinsufficient AppPs1 mice (Sirt3(+/-)AppPs1) exhibit early epileptiform EEG activity and seizure. Both male and female Sirt3(+/-)AppPs1 mice were observed to die prematurely before 5 months of age. When comparing male mice among different genotypes, Sirt3 haploinsufficiency renders GABAergic interneurons in the cerebral cortex vulnerable to degeneration and associated neuronal network hyperexcitability. Feeding Sirt3(+/-)AppPs1 AD mice with a ketone ester-rich diet increases SIRT3 expression and prevents seizure-related death and the degeneration of GABAergic neurons, indicating that the aggravated GABAergic neuron loss and neuronal network hyperexcitability in Sirt3(+/-)AppPs1 mice are caused by SIRT3 reduction and can be rescued by increase of SIRT3 expression. Consistent with a protective role in AD, SIRT3 levels are reduced in association with cerebral cortical A beta pathology in AD patients. In summary, SIRT3 preserves GABAergic interneurons and protects cerebral circuits against hyperexcitability, and this neuroprotective mechanism can be bolstered by dietary ketone esters.