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 脑内表观遗传基因控制机制受损，涉及组蛋白乙酰化减少 水平会导致严重的认知缺陷，这是大多数神经退行性变的标志 疾病，包括阿尔茨海默病(AD)。因此，已确定的神经表观遗传修饰 到目前为止，组蛋白乙酰化已经被明确地与通过调节促进学习和记忆有关 神经元中通过染色质包装控制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中心重要性，特异组蛋白 产生这些神经表观遗传标记的乙酰基转移酶(HATS)及其作用机制 神经表观遗传基因在大脑中的控制在很大程度上仍然未知。我们生成了功能强大的Tip60；应用程序 果蝇模型系统，使我们能够在AD下调节神经回路中Tip60 HAT的水平 相关淀粉样前体蛋白(APP)神经退行性疾病，体内。它的使用让我们兴奋不已 发现Tip60对认知过程是关键的，基于它在神经表观遗传基因控制和 值得注意的是，促进了对大脑早期受损的多个认知神经回路的神经保护 AD相关的神经退行性进展。此外，我们新的初步研究表明，Tip60帽子 人类AD海马区的认知基因控制功能受损。我们的发现奠定了坚实的基础 这项提议的基础工作和我们这个项目的目标是确定Tip60 HAT背后的机制 利用苍蝇和小鼠AD模型在神经保护性基因控制中的作用，并确定这些Tip60如何 人类阿尔茨海默病患者大脑中的表观遗传过程出错。我们假设Tip60促进 阿尔茨海默病病理过程中的神经保护--通过对大脑中的表观遗传学基因集进行重新编程 它们共同防止突触损伤和细胞凋亡，从而促进认知 功能。使用基于分子、细胞、生化和染色质的技术组合，以及 行为分析，在目标1A中，我们将使用我们的Tip60；APP和Tip60；Aβ42飞行模型来识别完整的 Tip60表观遗传重编程基因，并验证其在哺乳动物Tip60表观遗传中的保守性 老鼠的大脑。在目标1B中，我们将测试这些Tip60神经保护基因是否具有表观遗传学 正如我们预测的那样，人类阿尔茨海默病大脑中的错误调控。在目标2a中，我们将剖析转录 利用苍蝇和小鼠AD研究Tip60如何在表观遗传学上重新编程神经保护基因的机制 模特们。在Aim 2B中，我们将测试这些相同的Tip60转录调控复合体是否被破坏 在人类的AD大脑中，正如我们预测的那样。我们的研究将为新的Tip60表观遗传学提供广泛的见解 阿尔茨海默病等人类神经退行性疾病的潜在机制，以及新的 对基于HAT的药物设计的理解对认知障碍的早期治疗干预。

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