Elucidating the role of microglia and neurotrophin receptor p75 on neuronal degeneration in frontotemporal dementia

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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.