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

摘要 衰老是认知能力下降和痴呆的重要危险因素。随着人类平均寿命的增加 为了延长寿命，需要保护老化的大脑免受认知能力下降的影响，并降低神经退行性疾病的风险。 在大脑中与年龄相关的重要变化中，神经元容易变性， 疾病，是表观遗传控制的丧失，导致功能失调的基因表达。这些表观遗传变化 有可能成为逆转的目标，以预防或改善与年龄相关的衰退。组蛋白 乙酰化对于调节与基因激活相关的表观遗传景观至关重要， 它依赖于乙酰辅酶A合成酶2（ACSS 2）的活性。我们发现ACSS 2， 它产生乙酰辅酶A，在海马神经元中与染色质结合，并为海马神经元提供乙酰辅酶A。 组蛋白乙酰转移酶CBP用于学习和记忆。此外，ACSS 2敲除（KO）小鼠具有 影响了学习和记忆这些发现强调了ACSS 2对大脑功能的显着作用。 因此，我假设增强神经元中ACSS 2依赖的染色质过程将赋予 对由于衰老和阿尔茨海默病（AD）引起的认知下降和表观基因组功能障碍的恢复力。 在这里，我将研究ACSS 2依赖的染色质过程的增强是否可以保护神经元 对抗小鼠中与年龄和疾病相关的表观基因组失调和认知能力下降。我的目标是（1） 确定ACSS 2上调是否增强神经元功能并增加对年龄相关性神经元损伤的恢复力。 认知下降，和（2）确定ACSS 2上调是否赋予对AD的恢复力。我会上调 ACSS 2在人诱导性多能干细胞（iPSC）衍生的皮质神经元中的表达并研究ACSS 2的作用 在神经元活动期间，对染色质可接近性、基因表达和组蛋白乙酰化的上调。我会 还检测了ACSS 2上调对改善原代小鼠神经元中AD-tau相关病理的作用 用人AD-tau转染。最后，我将研究是否有可能改善老年小鼠的认知功能 脑与ACSS 2的组织特异性上调，并评估对AD-tau相关痴呆的影响， AD小鼠模型。总的来说，这些研究将促进我们对分子机制的理解， ACSS 2依赖性组蛋白乙酰化在神经元中的功能和ACSS 2依赖性特征， 保持认知功能。由于表观遗传代谢机制可以用小分子靶向， 这项工作为保护大脑免受衰老的侵害提供了新的方法基础。

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.