Enhancing neuronal resilience to aging and degeneration via the epigenetic-metabolic axis

通过表观遗传代谢轴增强神经元对衰老和退化的抵抗力

• 批准号: 10679706
• 负责人: Naemeh Pourshafie
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679706
• 关键词: Acetate-CoA Ligase; Acetyl Coenzyme A; Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Binding; Brain; Cell Culture Techniques; Chromatin; Cognitive; Complement; Dementia; Disease; Enzymes; Epigenetic Process; Foundations; Functional disorder; Gene Activation; Gene Expression; Genes; Genetic; Genome; Goals; Hippocampus; Histone Acetylation; Human; Impaired cognition; Impairment; Incidence; Induced pluripotent stem cell derived neurons; Knockout Mice; Learning; Longevity; Memory; Metabolic; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pathology; Predisposition; Prevalence; Process; Risk; Risk Factors; Role; Sorting; Tauopathies; Tissues; Transfection; Up-Regulation; Wild Type Mouse; Work; age related; aged; aging brain; cell type; cognitive ability; cognitive change; cognitive function; cognitive performance; epigenetic regulation; epigenomics; gene function; histone acetyltransferase; improved; induced pluripotent stem cell; insight; mouse model; multiple omics; neural; novel strategies; preservation; prevent; promote resilience; resilience; small molecule; tau Proteins; tau mutation; transcriptomics

ABSTRACT Aging is a significant risk factor for cognitive decline and dementia. With an increase in the average human lifespan, there is a need to protect the aging brain from cognitive decline and lower the risk of neurodegeneration. Among the important age-related changes in the brain that renders neurons susceptible to degeneration and disease, are the loss of epigenetic control leading to dysfunctional gene expression. These epigenetic changes have the potential to be targeted for reversal to prevent or ameliorate age-associated declines. Histone acetylation is crucial to the regulation of the epigenetic landscape associated with gene activation required for memory and is dependent on the activity of Acetyl CoA synthetase 2 (ACSS2). We have discovered that ACSS2, which generates acetyl-CoA, is chromatin bound in hippocampal neurons and provides acetyl-CoA for the histone acetyltransferase CBP for learning and memory. Furthermore, ACSS2 knockout (KO) mice have compromised learning and memory. These findings underscore the remarkable role of ACSS2 for brain function. Hence, I hypothesize that enhancing ACSS2-dependent chromatin processes in neurons will confer resilience to cognitive decline and epigenomic dysfunction due to aging and Alzheimer's disease (AD). Here I will investigate whether enhancement of ACSS2-dependent chromatin processes can protect neurons against age- and disease-associated epigenomic dysregulation and cognitive decline in the mouse. I aim to (1) Determine whether ACSS2 upregulation enhances neuronal function and increases resilience to age-associated cognitive decline, and (2) Determine whether ACSS2 upregulation confers resilience to AD. I will upregulate ACSS2 in human induced pluripotent stem cells (iPSC)-derived cortical neurons and study the effect of ACSS2 upregulation on chromatin accessibility, gene expression, and histone acetylation during neuronal activity. I will also examine the effect of ACSS2 upregulation to ameliorate AD-tau-related pathology in primary mouse neurons transfected with human AD-tau. Lastly, I will examine if it is possible to improve cognitive function in aged mouse brain with tissue specific upregulation of ACSS2 and assess the effects on AD-tau-associated dementia in an AD mouse model. Overall, these studies will advance our understanding of the molecular mechanisms and function of ACSS2-dependent histone acetylation in neurons and ACSS2-dependent features that could preserve cognitive function. As epigenetic-metabolic mechanisms can be targeted with small molecules, this work provides the foundation for new approaches to protect the brain against the onslaughts of aging.

抽象的 衰老是认知能力下降和痴呆症的重要危险因素。人类普通人的增加 寿命，有必要保护衰老的大脑免受认知能力下降并降低神经退行性的风险。 在与年龄相关的重要变化中，使神经元容易变性和 疾病是表观遗传控制的丧失导致基因表达功能失调的。这些表观遗传变化 有可能将逆转的目标定位为预防或改善与年龄相关的下降。组蛋白 乙酰化对于与与基因激活相关的表观遗传景观至关重要 记忆并取决于乙酰COA合成酶2（ACSS2）的活性。我们发现ACSS2， 产生乙酰辅酶A，是染色质，是在海马神经元中结合的，并为乙酰辅酶A提供了乙酰辅酶A 组蛋白乙酰转移酶CBP用于学习和记忆。此外，ACSS2敲除（KO）小鼠具有 受损的学习和记忆。这些发现强调了ACSS2在脑功能中的显着作用。 因此，我假设在神经元中增强ACSS2依赖性染色质过程将授予 由于衰老和阿尔茨海默氏病（AD）引起的认知能力下降和表观基因组功能障碍的韧性。 在这里，我将调查ACSS2依赖性染色质过程的增强是否可以保护神经元 针对小鼠年龄和疾病相关的表观基因组失调和认知下降。我的目标是（1） 确定ACSS2上调是否增强了神经元功能并提高了对年龄相关的弹性 认知能力下降，（2）确定ACSS2上调是否赋予对AD的弹性。我会上调 人类诱导多能干细胞（IPSC）衍生的皮质神经元中的ACSS2研究ACSS2的作用 神经元活性期间染色质访问，基因表达和组蛋白乙酰化的上调。我会 还要检查ACSS2上调对原代小鼠神经元中与AD-TAU相关的病理的影响 用人类ad-tau转染。最后，我将检查是否有可能改善老年鼠标的认知功能 大脑具有组织特异性ACSS2的特定上调，并评估对AD-TAU相关痴呆的影响 AD鼠标模型。总体而言，这些研究将促进我们对分子机制和 ACSS2依赖性组蛋白乙酰化在神经元和ACSS2依赖性特征中的功能 保留认知功能。由于可以用小分子来靶向表观遗传代谢机制，因此 工作为保护大脑免受衰老的猛烈袭击提供了新方法的基础。