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: 10688812
• 负责人: Emmanouil Maragkakis
• 金额: $ 6.59万
• 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/10688812
• 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，发展为严重的认知功能障碍。阿尔茨海默病的病理特征是淀粉样蛋白(A)斑块、神经原纤维缠结、神经元突触逐渐丧失和记忆丧失。人类脑功能成像研究表明，在认知障碍变得明显之前，神经网络高兴奋性（NNH）发生在疾病进展早期的易感脑区。Sirtuin3 （SIRT3）是一种依赖于NAD+的去乙酰化酶，它可以从线粒体蛋白的赖氨酸残基中去除乙酰基，参与氧化应激反应。SIRT3单倍不足加重了小鼠AD模型中gaba能中间神经元和NNH的损失。我们之前发现SIRT3在保护神经元免受兴奋毒性和代谢应激方面的新作用，其机制涉及增强线粒体超氧化物的去除和细胞凋亡的抑制。最近，我们使用SIRT3单倍不足的AppPs1突变体（SIRT3 +/AppPs1或SIRT3 AD小鼠）转基因AD小鼠，发现SIRT3水平降低会导致大脑皮层中间神经元的显著丧失，并加剧神经元回路的高兴奋性。这些结果强调了SIRT3通过介导中间神经元存活和相关神经元网络活动来维持线粒体功能的关键作用。在这项提议中，我们的目标是通过对Sirt3+/AppPs1转基因小鼠的易感脑区进行直接RNA测序来研究转录组学特征，探索神经元高兴奋性和过早死亡的分子机制。具体来说，我们计划a)确定Sirt3 AD小鼠皮层中的时间基因表达程序b)解剖Sirt3+/-介导的活性氧代谢，RNA氧化和衰变的失调的影响c)确定Sirt3+/-介导的小鼠大脑中转录变化的空间分布。为了实现这些目标，我们让小鼠衰老，对从皮层提取的RNA进行直接测序，并对产生的测序数据进行计算分析。