Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

总结 阿尔茨海默病（AD）影响全世界超过5000万人。绝大多数患者，AD 在除高龄以外没有任何已知病因的情况下零星发生。尽管AD 已经研究了世纪，其发病机制仍然没有完全了解， 阻止或逆转疾病进展的方法尚不可行。与许多年龄相关的发病率相似， 在癌症中，AD发病被认为是由环境、基因组和衰老相关的多重打击引起的。 因素为了更好地了解人类衰老和AD之间的细胞和分子相互作用， 在发病机制中，直接从AD患者成纤维细胞转化的诱导神经元（iN）提供了独特的可能性， 在人类年龄相当的神经元模型中建模和研究疾病。 盖奇博士和默滕斯博士周围的团队最近表明，人类AD的直接转化 患者来源的成纤维细胞转化为诱导神经元（iN）保留了细胞老化和散发性AD的特征， 允许检测细胞病理和疾病驱动因素。神经元发育不全代表 iNs中AD相关的基本细胞状态和癌症相关丙酮酸激酶M2（PKM 2）剪接 变体作为一个关键的球员出现，妥协成熟的神经元代谢和神经元的身份。PKM2 通过细胞质中的代谢变化促进神经元的脆弱性和去分化， 细胞核中的表观遗传过程，但这两种机制的相对贡献仍然难以捉摸， 可能在癌细胞和有丝分裂后神经元之间有很大不同。了解AD中的PKM 2， 开发PKM导向的治疗方法，更多关于（1）神经元PKM 2 PKM 2在老年人中的基本细胞生物学功能 神经元，和（3）PKM受损的神经元和它们的胶质环境之间的串扰是必需的。 该项目将挑战癌症和AD之间共有致病途径的重要性， 评估AD背景下年龄依赖性受损的神经元。首先，团队将研究 癌症相关PKM 2阳性神经元和AD病理学之间的关系。第二、 PKM 2失衡对患者特异性神经元代谢状态和神经元命运稳定性的机制影响 iN将通过基于转基因和基因组编辑的方法进行评估。三、药理学 作为开发PKM 2靶向治疗AD的基础， 杠杆。第四，使用一种新的基于人类iN的三维多细胞模型，该团队将研究 在代谢挑战的iN及其代谢串扰的背景下神经元-星形胶质细胞偶联 人类星形胶质细胞这四个目标的最终目标是深入了解油井的作用- 在年龄相关的神经退行性变中建立了癌症蛋白PKM 2，并利用这一知识开发 AD的治疗策略。

SUMMARY Alzheimer’s disease (AD) affects over 50 million people worldwide. The vast majority of patients, AD develops sporadically in the absence of any known etiology other than advanced age. Despite the fact that AD has been studied for over a century, its pathogenesis is still not completely understood, and drugs that could stop or reverse the disease progression are not yet available. Similar to the age-dependent incidence of many cancers, AD onset is believed to be caused by multiple hits of environmental, genomic, and aging-related factors. To better understand the cellular and molecular interactions between human aging and AD pathogenesis, induced neurons (iNs) directly converted from AD patient fibroblasts offer unique possibilities to model and study the disease in a human age-equivalent neuronal model. The teams around Dr. Gage and Dr. Mertens have recently shown that direct conversion of human AD patient-derived fibroblasts into induced neurons (iNs) preserves signatures of cell aging and sporadic AD and allows for the detection of cellular pathologies and disease drivers. Neuronal hypo-maturity represents a fundamental AD-related cellular state in iNs, and the cancer-associated Pyruvate Kinase M2 (PKM2) splice variant emerged as a key player that compromises mature neuronal metabolism and neuronal identity. PKM2 promotes neuronal vulnerability and de-differentiation via metabolic changes in the cytoplasm, and via epigenetic processes in the nucleus, but the relative contribution of the two mechanisms remains elusive and might differ substantially between cancer cells and post-mitotic neurons. To understand PKM2 in AD, and to develop PKM-directed therapeutics, more knowledge regarding (1) the relationship between neuronal PKM2 and hallmarks of AD in the human brain, (2) the fundamental cell biological functions of PKM2 in aged human neurons, and (3) the crosstalk between PKM-compromised neurons and their glial environment is needed. This project will challenge the importance of shared pathogenic pathways between cancer and AD, and assess age-dependently compromised neurons in the context of AD. First, the team will study the relationship between cancer-related PKM2-positive neurons and AD pathology in the post-mortem human brain. Second, the mechanistic impact of PKM2 imbalance on the metabolic state and neuronal fate stability of patient-specific iNs will be assessed by transgene- and genome editing-based approaches. Third, pharmacological compounds from the cancer field as a basis for developing PKM2-targeted therapeutics for AD will be leveraged. Fourth, using a novel human iN-based three-dimensional multicellular model, the team will study neuron-astrocyte coupling in the context of metabolically challenged iNs and their metabolic crosstalk with human astrocytes. The ultimate goals of these four aims are to gain insight into the roles of the well- established cancer protein PKM2 in age-related neurodegeneration and to exploit this knowledge to develop therapeutic strategies against AD.