Gene and transcriptional profiles in aging mice for Sirtuin 3 haploinsufficiency Alzheimers disease model

Sirtuin 3 单倍体不足阿尔茨海默病模型的衰老小鼠基因和转录谱

• 批准号: 10471679
• 负责人: Emmanouil Maragkakis
• 金额: $ 21.36万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471679
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Brain; Brain imaging; Brain region; Cerebrum; Cessation of life; Data; Deacetylase; Disease Progression; Excision; Gene Expression; Gene Expression Profile; Genetic Transcription; Health; Hippocampus (Brain); Human; Impaired cognition; Inhibition of Apoptosis; Interneurons; Lysine; Mediating; Memory Loss; Metabolic stress; Metabolism; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oxidative Stress; Pathologic; Pathology; RNA; Reactive Oxygen Species; Role; Seizures; Sirtuins; Spatial Distribution; Superoxides; Synapses; Transgenic Mice; Transgenic Organisms; design; effective therapy; excitotoxicity; imaging study; mild cognitive impairment; mouse model; mutant; neuron loss; neuronal circuitry; novel; novel therapeutics; oxidation; premature; programs; response; transcriptome sequencing; transcriptomics

Alzheimers Disease (AD) is a neurodegenerative disorder that initially manifests as mild cognitive impairment and progresses to severe cognitive dysfunction. The pathological hallmarks of AD are characterized by the presence of amyloid-beta (A) plaques, neurofibrillary tangles, gradual loss of neuronal synapse, and memory loss. Functional brain imaging studies in human has shown that neuronal network hyperexcitability (NNH) occurs in vulnerable brain regions early in the disease progression before the cognitive impairment becomes evident. Sirtuin3 (SIRT3) is a NAD+ dependent deacetylase which removes the acetyl group from the Lysine residue of mitochondrial proteins that are involved in response to oxidative stress. SIRT3 haploinsufficiency aggravates loss of GABAergic interneurons and NNH in mouse model of AD. We previously discovered a novel role of SIRT3 in protecting neurons against excitotoxic and metabolic stress by mechanisms involving enhanced removal of mitochondrial superoxide and inhibition of apoptosis. More recently, we showed that reduced levels of SIRT3 causes significant loss of cerebral cortical interneurons and aggravates neuronal circuit hyperexcitability using SIRT3 haploinsufficient AppPs1 mutant (Sirt3+/AppPs1 or sirt3 AD mice) transgenic AD mice. These results underscore the critical role of SIRT3 in sustaining mitochondria function by mediating interneuron survival and associated neuronal network activity. In this proposal, we aim to explore the molecular mechanisms underlying neuronal hyperexcitability and premature death by investigating the transcriptomic profile using direct RNA sequencing of vulnerable brain regions of Sirt3+/AppPs1 transgenic mice. Specifically, we plan to a) identify the temporal gene expression program in the cortex of Sirt3 AD mice b) dissect the effect of Sirt3+/--mediated deregulation of Reactive Oxygen Species metabolism, RNA oxidation and decay c) identify the spatial distribution of Sirt3+/--mediated transcriptional changes in the mouse brain. To address these objectives, we have mice aging, perform direct sequencing of RNA extracted from the cortex and analyze the produced sequencing data computationally.

阿尔茨海默病（AD）是一种神经退行性疾病，最初表现为轻度认知障碍，并进展为严重的认知功能障碍。AD的病理学标志的特征在于存在淀粉样蛋白-β（A）斑块、神经元缠结、神经元突触的逐渐丧失和记忆丧失。人类脑功能成像研究表明，在疾病进展的早期，在认知障碍变得明显之前，神经元网络过度兴奋（NNH）发生在脆弱的大脑区域。Sirtuin 3（SIRT 3）是NAD+依赖性脱乙酰酶，其从参与响应氧化应激的线粒体蛋白的赖氨酸残基去除乙酰基。SIRT 3单倍不足导致AD小鼠模型中GABA能中间神经元和NNH的丢失我们先前发现SIRT 3在保护神经元免受兴奋性毒性和代谢应激中的新作用，其机制涉及增强线粒体超氧化物的清除和抑制细胞凋亡。最近，我们发现SIRT 3水平降低导致大脑皮层中间神经元的显著损失，并使用SIRT 3单倍不足的AppPs 1突变体（Sirt 3 +/AppPs 1或sirt 3 AD小鼠）转基因AD小鼠来增强神经元回路的过度兴奋性。这些结果强调了SIRT 3通过介导中间神经元存活和相关神经元网络活动在维持线粒体功能中的关键作用。在这个建议中，我们的目标是探索神经元过度兴奋和过早死亡的分子机制，通过研究转录谱使用直接RNA测序的Sirt 3 +/AppPs 1转基因小鼠的脆弱的大脑区域。具体而言，我们计划a）鉴定Sirt 3 AD小鼠皮质中的时间基因表达程序B）剖析Sirt 3 +/-介导的活性氧代谢、RNA氧化和衰变的失调的影响c）鉴定Sirt 3 +/-介导的转录变化在小鼠脑中的空间分布。为了解决这些目标，我们让小鼠衰老，对从大脑皮层提取的RNA进行直接测序，并通过计算分析产生的测序数据。