iPSC from British and Danish dementias: new discovery tools for brain amyloidoses

描述（由申请人提供）：将原代真皮成纤维细胞重编程为诱导多能干细胞（iPSCs）最近被证明是神经退行性疾病患者产生可存活神经元的工具。这项技术为建立体外模型来研究相关人类细胞类型的疾病病理生理学提供了巨大的希望，否则这些模型是不可能获得的。家族性英国和丹麦痴呆（分别为FBD和FDD）是常染色体显性遗传病，与阿尔茨海默病（AD）的许多临床和神经病理特征非常相似，包括实质淀粉样蛋白和前淀粉样蛋白病变，广泛的脑淀粉样血管病和神经原纤维缠结在形态和免疫化学上与AD难以区分。值得注意的是，从FBD沉积物中分离的淀粉样蛋白亚基- abri -和FDD病变- adan -在结构上与阿尔茨海默病无关，这清楚地表明不同的淀粉样蛋白肽可能引发类似的神经病理改变，导致相同的情况：caa相关的微血管功能障碍，神经元丢失和痴呆。因此，这些家族性疾病构成了有希望的替代范例，以更好地了解淀粉样蛋白在疾病发病机理的复杂机制中的作用。鉴于AD、FBD和FDD在临床和神经病理学上存在许多相似之处，我们建议：i)利用从FBD和FDD患者以及两种疾病的非携带者兄弟姐妹中获得的真皮成纤维细胞，使用重复mRNA转染（一种更安全的非dna整合技术，已被研究小组成功使用），生成并表征iPSC系；ii)进一步区分

DESCRIPTION (provided by applicant): Reprogramming of primary dermal fibroblasts into induced pluripotent stem cells (iPSCs) has recently proven to be instrumental for the generation of viable neurons derived from patients with neurodegenerative disorders. This technology holds tremendous promise for the creation of in vitro models to study disease pathophysiology in relevant human cell types that would otherwise be impossible to obtain. Familial British and Danish dementias (FBD and FDD, respectively) are autosomal dominant conditions that closely resemble many clinical and neuropathological features of Alzheimer's disease (AD) including parenchymal amyloid and pre- amyloid lesions, widespread cerebral amyloid angiopathy and neurofibrillary tangles morphologically and immunochemically indistinguishable from those in AD. Notably, the amyloid subunits isolated from FBD deposits -ABri- and FDD lesions -ADan- are structurally unrelated to the Alzheimer's A¿, a clear indication that different amyloid peptide could trigger similar neuropathological changes leading to the same scenario: CAA-related microvascular dysfunction, neuronal loss and dementia. Thus, these familial disorders constitute promising alternative paradigms to better understand the role of amyloid in the complex mechanisms of disease pathogenesis. In view of the many clinical and neuropathological similarities between AD, FBD and FDD, we are proposing i) to generate and characterize iPSC lines from dermal fibroblasts obtained from a cohort of FBD and FDD patients as well as from non-carrier siblings of both disorders using repetitive mRNA transfections, a safer non- DNA-integrating technology successfully used by the research team; and ii) to further differentiate the newly generated iPSCs into viable and functional neurons and endothelial cells characterized through well- established morphological, molecular and biological criteria. We anticipate that these iPSC-derived mature cells will constitute excellent candidates to study specific molecular and temporal aspects linked to FBD and FDD disease phenotypes. Moreover, they will have a broader impact in the field of neurodegenerative disorders, extending beyond these rare diseases into the field of AD, providing invaluable options for a better understanding of the mechanisms that modulate APP processing, A¿ homeostasis and the process of tau hyperphosphorylation, serving as alternative paradigms for high throughput drug screening platforms, and assisting with the identification of cross-talk pathways connecting CAA-associated blood brain barrier dysfunction and development of microhemorrhages with changes in the neurovascular unit and cognitive impairment. This proposal represents a collaborative effort from investigators of New York University School of Medicine and the University of California, Irvine and builds on the complementary expertise of the participating researchers and their long-standing interest in the molecular pathogenesis of cerebral amyloid disorders.