Elucidating the Role of Microglia and Neurotrophin Receptor p75 on Neuronal Degeneration in Frontotemporal Dementia

额颞性痴呆(FTD)由一组早发性神经退行性疾病组成，其特征是 中枢神经系统广泛的神经元变性导致行为和语言障碍 和认知力。至于其他形式的痴呆症，人们对神经变性的机制知之甚少。 而且治疗的选择仍然不存在。越来越多的证据表明，非细胞自主 机制在疾病的发展过程中起着重要作用，小胶质细胞在疾病的发展过程中起着重要作用 患者大脑的病理变化。FTD患者脑内小胶质细胞被强烈激活 而它们的激活似乎在神经细胞死亡的区域最高。此外，成像研究也有 证明小胶质细胞的激活在疾病发展的早期就开始了。因此，很有可能 小胶质细胞直接导致FTD的神经元变性，令人惊讶的是，这一作用在 田野。这个K08职业发展项目致力于阐明这种由小胶质细胞介导的非细胞- 结合包括单核RNA在内的分子分析研究神经退变的自主机制 利用患者来源的FTD动态人类干细胞模型对死后脑组织进行测序 诱导多能干细胞(IPSCs)。这项研究的总体目标是表征细胞内的变化 FTD中神经元和小胶质细胞的程序以及了解患者小胶质细胞是否以及如何影响完整性 这种疾病中的相邻神经元。在我们初步数据的鼓舞下，我们假设神经营养因子 在这方面，p75NTR受体通过促进处于危险状态的神经元的死亡而发挥重要作用。我们也 认为FTD患者来源的神经元对细胞死亡的易感性增加，并进一步加剧 通过神经胶质细胞。这项研究将对IPSC来源的FTD和基因校正的控制神经元进行共培养试验 在体外(特定目标1)，将这些细胞移植到免疫低下小鼠的脑内(特定目标 2)和FTD患者死后脑组织的单细胞研究(目标3)。在K08大奖期间 在此期间，申请者还将接受关于人类细胞和组织的单核RNA测序的培训 来自FTD患者。这个项目将促进我们对小胶质细胞和神经营养因子的作用的理解 信号在FTD发病机制中的作用，长期目标是更好地理解和潜在的治疗 解决这种疾病的潜在机制。

Frontotemporal dementia (FTD) comprises a group of early-onset neurodegenerative diseases characterized by widespread neuronal degeneration in the central nervous system leading to impairment of behavior, language and cognition. As for other forms of dementias, mechanisms of neurodegeneration are only poorly understood and curative treatment options still do not exist. There is growing evidence that non-cell-autonomous mechanisms play an important role during disease development and that microglial cells significantly contribute to pathologic changes in patients' brains. Microglial cells are strongly activated in the brains of patients with FTD and their activation appears to be highest in areas of neuronal cell death. Also, imaging studies have demonstrated that microglial activation begins early during disease development. Thus, it is very likely that microglia directly contribute to neuronal degeneration in FTD, a role that has surprisingly been understudied in the field. This K08 career development project sets out to elucidate such microglia-mediated, non-cell- autonomous mechanisms of neurodegeneration by combining molecular analyses including single-nucleus RNA sequencing in postmortem brain tissue with a dynamic human stem cell model of FTD using patient-derived induced pluripotent stem cells (iPSCs). The overall goal of this study is to characterize changes in cellular programs in neurons and microglia in FTD and to understand if and how patient microglia influence the integrity of adjacent neurons in this disease. Encouraged by our preliminary data, we hypothesize that the neurotrophin receptor p75NTR plays has an important role in this context by promoting death of neurons at risk. We also propose that FTD-patient derived neurons carry an increased susceptibility to cell death that is further aggravated by glia cells. This study will apply co-culture assays on iPSC-derived FTD and gene-corrected control neurons in vitro (Specific Aim 1), transplantation of these cells into the brains of immunocompromised mice (Specific Aim 2) and single cell studies on postmortem brain tissue from FTD patients (Specific Aim 3). During the K08 Award period, the applicant will also receive training in single-nucleus RNA sequencing on human cells and tissues from patients with FTD. This project will advance our understanding of the role of microglia and neurotrophin signaling in the pathogenesis of FTD with the long-term goal to better understand and potentially therapeutically address the underlying mechanisms of this disease.