Mechanisms underlying Tip60 HAT action in neuroprotection of cognitive function

Tip60 HAT 认知功能神经保护作用的机制

• 批准号: 10176606
• 负责人: FELICE ELEFANT
• 金额: $ 38.84万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176606
• 关键词: Address; Adult; Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-42; Amyloid beta-Protein Precursor; Apoptotic; Behavioral; Behavioral Assay; Binding; Biochemical; Biological Models; Brain; Cell Death; Chromatin; Cognition; Cognitive; Cognitive deficits; Complex; DNA Binding; Data Set; Disease; Drosophila Proteins; Drug Design; Epigenetic Process; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; HDAC2 gene; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Human; Impaired cognition; Impairment; Learning; Link; Mediating; Memory; Modeling; Modification; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Pathologic Processes; Pharmacological Treatment; Pilot Projects; Process; Protein Acetylation; Publishing; RNA; Regulation; Research; Role; Solid; Synapses; Techniques; Testing; Therapeutic; Therapeutic Intervention; base; brain tissue; cognitive function; cognitive process; epigenomics; fly; functional restoration; genome-wide; genomic locus; histone acetyltransferase; in vivo; insight; neural circuit; neuropathology; neuroprotection; novel; programs; recruit; relating to nervous system; transcription factor; virtual

ABSTRACT Impairment of epigenetic gene control mechanisms in the brain involving reduced histone acetylation levels causes significant cognitive deficits that are a debilitating hallmark of most neurodegenerative disorders, including Alzheimer's disease (AD). Accordingly, of the neural epigenetic modifications identified to date, histone acetylation has been unequivocally linked to facilitating learning and memory by regulating cognition gene expression programs via chromatin packaging control in neurons. Nevertheless, despite the central importance of histone acetylation in higher order brain function, the specific histone acetyltransferases (HATs) that generate these neuroepigenetic marks and their mechanisms of action in neural epigenetic gene control in the brain remain largely unknown. We generated a robust Tip60;APP Drosophila model system that enables us to modulate Tip60 HAT levels in neural circuits of choice under AD associated amyloid precursor protein (APP) neurodegenerative conditions, in vivo. Its use led to our exciting discovery that Tip60 is critical for cognitive processes based on its role in neural epigenetic gene control and remarkably, promotes neuroprotection for multiple cognitive neural circuits impaired in the brain during early AD associated neurodegenerative progression. Further, our new preliminary studies indicate that Tip60 HAT function in cognitive gene control is impaired in the human AD hippocampus. Our findings have laid a solid groundwork for this proposal and our goal for this project is to identify the mechanisms underlying Tip60 HAT action in neuroprotective gene control using fly and mouse AD models, and to determine how these Tip60 epigenetic processes go awry in the brains of human AD patients. We hypothesize that Tip60 promotes neuroprotection during the AD pathological process by epigenetically reprogramming gene sets in the brain that together protect against synaptic impairment and apoptotic cell death, and thus promote cognitive function. Using a combination of molecular, cellular, biochemical and chromatin based techniques, along with behavioral assays, in Aim 1A we will use our Tip60;APP and Tip60;Aβ42 fly models to identify the full array of Tip60 epigenetic reprogrammed genes, and verify their mammalian Tip60 epigenetic conservation in the mouse brain. In Aim 1B we will test whether these Tip60 neuroprotective genes are epigenetically misregulated in the human AD brain, as we predict. In Aim 2A, we will dissect the transcriptional mechanisms for how Tip60 epigenetically reprograms neuroprotective genes using fly and mouse AD models. In Aim 2B we will test whether these same Tip60 transcriptional regulatory complexes are disrupted in the human AD brain, as we predict. Our studies will provide broad insights into novel Tip60 epigenetic mechanisms underlying human neurodegenerative disorders such as Alzheimer's disease, and new understanding into HAT based drug design for early therapeutic intervention of cognitive deficits.

摘要 组蛋白乙酰化减少导致脑中表观遗传基因控制机制受损 水平会导致严重的认知缺陷，这是大多数神经退行性疾病的衰弱标志 疾病，包括阿尔茨海默病（AD）。因此，在鉴定出的神经表观遗传修饰中， 迄今为止，组蛋白乙酰化已明确与促进学习和记忆有关， 通过染色质包装控制神经元中的认知基因表达程序。然而，尽管 组蛋白乙酰化在高级脑功能中的核心重要性， 产生这些神经表观遗传标记的乙酰转移酶（HAT）及其在神经系统中的作用机制 大脑中的神经表观遗传基因控制在很大程度上仍然未知。我们生成了一个强大的Tip 60;APP 果蝇模型系统，使我们能够调节AD下选择的神经回路中的Tip 60 HAT水平 相关的淀粉样前体蛋白（APP）神经退行性疾病。它的使用让我们兴奋不已 发现Tip 60基于其在神经表观遗传基因控制中的作用对认知过程至关重要， 值得注意的是，促进了早期脑损伤中多个认知神经回路的神经保护作用。 AD相关神经退行性进展。此外，我们新的初步研究表明，Tip 60 HAT 在人类AD海马中，认知基因控制的功能受损。我们的发现为 本项目的目标是确定Tip 60 HAT的潜在机制 使用果蝇和小鼠AD模型进行神经保护基因控制，并确定这些Tip 60 表观遗传过程在人类AD患者的大脑中出错。我们假设Tip 60促进了 通过表观遗传学重编程脑中的基因集在AD病理过程中的神经保护作用 共同保护突触损伤和凋亡细胞死亡，从而促进认知功能 功能使用分子、细胞、生物化学和基于染色质的技术的组合，沿着 行为分析，在目标1A中，我们将使用我们的Tip 60;APP和Tip 60;Aβ42苍蝇模型来识别所有的 Tip 60表观遗传重编程基因，并验证其在哺乳动物中的Tip 60表观遗传保守性。 老鼠的大脑在Aim 1B中，我们将测试这些Tip 60神经保护基因是否是表观遗传学上的。 在人类AD大脑中失调，正如我们预测的那样。在目标2A中，我们将剖析 Tip 60如何利用果蝇和小鼠AD表观遗传学重新编程神经保护基因的机制 模型在目标2B中，我们将测试这些相同的Tip 60转录调控复合物是否被破坏， 在人类AD大脑中，正如我们预测的那样我们的研究将为新的Tip 60表观遗传学提供广泛的见解。 人类神经退行性疾病如阿尔茨海默病的潜在机制，以及新的 了解基于HAT的药物设计，用于认知缺陷的早期治疗干预。

项目成果

Amyloid-β Peptide Impact on Synaptic Function and Neuroepigenetic Gene Control Reveal New Therapeutic Strategies for Alzheimer's Disease.

• DOI: 10.3389/fnmol.2020.577622
• 发表时间: 2020
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Karisetty BC;Bhatnagar A;Armour EM;Beaver M;Zhang H;Elefant F
• 通讯作者: Elefant F

Exploring the Alzheimer's disease neuroepigenome: recent advances and future trends.

• DOI: 10.4103/1673-5374.317978
• 发表时间: 2022-03
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Zhang H;Elefant F
• 通讯作者: Elefant F

Tip60 protects against amyloid-β-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration.

• DOI: 10.1016/j.mcn.2020.103570
• 发表时间: 2020-12
• 期刊: Molecular and cellular neurosciences
• 作者: Zhang H;Karisetty BC;Bhatnagar A;Armour EM;Beaver M;Roach TV;Mortazavi S;Mandloi S;Elefant F
• 通讯作者: Elefant F