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

摘要 衰老是认知衰退和痴呆症的一个重要风险因素。随着人类平均年龄的增加 在人的一生中，有必要保护老化的大脑免受认知能力下降的影响，并降低神经退化的风险。 在大脑中与年龄相关的重要变化中，使神经元容易退化和 疾病，是指表观遗传控制的丧失，导致基因表达功能障碍。这些表观遗传变化 有可能成为逆转的目标，以防止或改善与年龄相关的下降。组蛋白 乙酰化对于调节与基因激活相关的表观遗传格局是至关重要的 并依赖于乙酰辅酶A合成酶2(ACSS2)的活性。我们发现ACSS2， 产生乙酰辅酶A，在海马神经元中与染色质结合，为 组蛋白乙酰转移酶CBP与学习和记忆。此外，ACSS2基因敲除(KO)小鼠 学习和记忆能力受损。这些发现强调了ACSS2对大脑功能的显著作用。 因此，我假设，增强神经元中依赖ACSS2的染色质过程将赋予 对衰老和阿尔茨海默病(AD)引起的认知衰退和表观基因组功能障碍的恢复力。 在这里，我将研究ACSS2依赖的染色质过程的增强是否可以保护神经元 对抗年龄和疾病相关的表观基因组失调和小鼠认知能力下降。我的目标是(1) 确定ACSS2上调是否增强神经元功能和增强对年龄相关的恢复能力 认知衰退，以及(2)确定ACSS2上调是否增强了对AD的韧性。我会升华的 ACSS2在人诱导的多能干细胞(IPSC)来源的皮质神经元中的表达及作用研究 神经元活动过程中染色质可及性、基因表达和组蛋白乙酰化的上调。这就做 同时检测ACSS2上调对改善原代小鼠神经元AD-tau相关病理的影响 人AD-tau基因转染组。最后，我将研究是否有可能改善老龄小鼠的认知功能 脑组织特异性上调ACSS2，并评估其对AD-tau相关性痴呆的影响 广告鼠标模型。总体而言，这些研究将促进我们对分子机制和 ACSS2依赖的组蛋白乙酰化在神经元中的作用以及ACSS2依赖的特征 保护认知功能。由于表观遗传-新陈代谢机制可以针对小分子，这 这项工作为保护大脑免受衰老冲击的新方法奠定了基础。

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.