AMYLOIDOGENIC INDUCTION OF CELLULAR SENESCENCE IN ALZHEIMER'S DISEASE

项目总结 细胞衰老是衰老的主要标志之一，描述的是细胞突然无法分裂。 衰老的细胞通常随着年龄的增长而积累，以响应物理和化学应激(基因组不稳定， 端粒磨损、辐射等)，尽管这些应激源与神经疾病之间的重叠 因为阿尔茨海默病(AD)目前尚不清楚。体外衰老实验常采用人工合成的方法 过氧化氢或辐射等可能与年龄相关的生理因素无关的应激源 阿尔茨海默病等疾病。此外，在体外观察到的衰老表型可能不是完全的模型。 在动态的生物系统中发生了什么。 可溶性淀粉样β寡聚体(Aβo)是阿尔茨海默病的一个重要标志，已被证明能有效地诱导 在各种脑细胞类型和环境中的衰老，与纤维抗体相反。βo被认为与 膜蛋白，随后信号下游聚集的相关淀粉样蛋白，如tau。事实上, 内源性Aβo的存在是AD模型和AD模型中疾病严重性的最强指标之一 生物体，这表明AD和细胞衰老之间的联系才刚刚开始探索。 为了研究这种联系，我们建议将金标准技术和单细胞组学相结合 数据来定义衰老的异质遗传和表观遗传特征，这些特征明显是 他们的归纳类型的功能。这样做还将产生强有力的信号和衰老的生物标记物 可用于人类组织病理表型的脑细胞。这些措施还将允许 用于比较不同的衰老行为，以帮助识别最相似的实验室来源的淀粉样蛋白 患者衍生的结构。我们将评估多个实验室衍生的Aβo结构，包括那些从 脂类位于大脑的主要病变区域。观察结果将协同配合 溶液生物物理实验和分子建模，为每个诱导剂提供类似的结构数据 打字。综上所述，这些测量将独特地描绘脑细胞的衰老情况，定义 内源性衰老诱导剂与实验室重组的衰老诱导剂之间的重叠，并突出了AD如何 风险受细胞衰老的影响。

PROJECT SUMMARY Cellular senescence, one of the major hallmarks of aging, describes the sudden inability for cells to divide. Senescent cells often accumulate with age, in response to physical and chemical stressors (genomic instability, telomere attrition, irradiation, etc.), though the overlap between these stressors and neurological diseases such as Alzheimer’s Disease (AD) is currently unknown. In-vitro experiments of senescence often utilize contrived stressors such as hydrogen peroxide or radiation, that may not be physiologically relevant for age-related diseases such as AD. Furthermore, the senescence phenotypes observed in vitro are likely not complete models for what is occurring in dynamic biological systems. Soluble amyloid-beta oligomers (Aβo), an important hallmark in AD, have been shown to potently induce senescence in a variety of brain cell types and environments, in contrast to fibrillar Ab. Aβo is thought to bind membrane proteins and subsequently signal downstream aggregation of related amyloids such as tau. In fact, the presence of endogenous Aβo is one of the strongest indicators of disease severity in AD models and organisms, suggesting a link between AD and cellular senescence that is only beginning to be explored. In order to study this association, we propose to combine gold-standard techniques and single-cell omics data in order to define heterogenous genetic and epigenetic signatures of senescence that are distinctly a function of their induction type. Doing so will also produce robust signatures and biomarkers of senescence in brain cells that can be utilized for the pathological phenotyping of human tissues. These measures will also allow for the comparison of disparate senescent behaviors to help identify lab-derived amyloids that best resemble patient-derived constructs. We will evaluate multiple lab-derived Aβo constructs, including those stabilized from lipids located in predominantly diseased regions of the brain. Observations would be synergistically coupled with solution biophysics experiments and molecular modeling, providing analogous structural data for each inducer type. Taken together, these measurements will uniquely profile senescence in brain cells, define the degree of overlap between endogenous senescence inducers and those reconstituted in the lab, and highlighting how AD risk is modulated by cellular senescence.