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

来自英国和丹麦痴呆症的 iPSC：大脑淀粉样变性的新发现工具

• 批准号: 8652006
• 负责人: JORGE A BUSCIGLIO
• 金额: $ 26.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652006
• 关键词: APP gene; Abrus; Affect; Alzheimer' s Disease; Amyloid; Amyloidosis; Animal Model; Autopsy; Biological; Biopsy; Blood - brain barrier anatomy; Blood Vessels; Brain; British; California; Cell Death; Cell Line; Cell model; Cells; Cerebral Amyloid Angiopathy; Cerebrum; Clinical; Collaborations; Complex; DNA; Dementia; Denmark; Deposition; Dermal; Development; Disease; Down Syndrome; Employee Strikes; Endothelial Cells; Endothelium; Exhibits; Familial disease; Fibroblasts; Functional disorder; Future; Generations; Genes; Goals; Hereditary Disease; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Institutes; Lead; Lesion; Link; London; Mediating; Messenger RNA; Modeling; Molecular; Mus; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurology; Neuronal Dysfunction; Neurons; New York; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Phenotype; Pluripotent Stem Cells; Preclinical Drug Evaluation; Presenile Alzheimer Dementia; Process; Production; Protein Precursors; RNA; Rare Diseases; Regulation; Reporting; Research; Research Personnel; Role; Siblings; Skin; Somatic Cell; Synapses; Technology; Tissues; Transfection; Transgenic Animals; Universities; University Hospitals; amyloid peptide; amyloid precursor protein processing; cell type; cerebrovascular; cohort; disease mechanisms study; disease phenotype; end stage disease; in vitro Model; induced pluripotent stem cell; innovation; interest; medical schools; nervous system disorder; neurofibrillary tangle formation; neuron loss; neurovascular unit; novel; public health relevance; relating to nervous system; secretase; tau Proteins; tau aggregation; tool

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 peptides 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.

原代真皮成纤维细胞重编程为诱导多能干细胞（iPSC）最近已证明 有助于产生来自神经退行性疾病患者的有活力的神经元。 这项技术为研究疾病病理生理学的体外模型的建立带来了巨大的希望 在相关的人类细胞类型，否则将不可能获得。英国和丹麦家族 痴呆（分别为FBD和FDD）是常染色体显性疾病，与许多 阿尔茨海默病（AD）的临床和神经病理学特征，包括实质淀粉样蛋白和前 淀粉样病变、广泛性脑淀粉样血管病和神经纤维缠结， 在免疫化学上与AD中的那些无区别。值得注意的是，从FBD分离的淀粉样蛋白亚基 沉积物-ABri-和FDD病变-ADan-在结构上与阿尔茨海默氏症A？无关，这是一个明确的迹象， 不同的淀粉样肽可以引发类似的神经病理学变化，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 有希望的替代范式，以更好地了解淀粉样蛋白在复杂的机制， 发病机理 鉴于AD、FBD和FDD之间的许多临床和神经病理学相似性，我们提出i） 从FBD和FDD的群组获得的真皮成纤维细胞产生和表征iPSC系 患者以及来自两种疾病的非携带者兄弟姐妹，使用重复mRNA转染， 研究团队成功使用的DNA整合技术;以及ii）进一步区分新的 将iPSC生成为活性和功能性神经元和内皮细胞，其特征在于， 建立了形态学、分子学和生物学标准。我们预计，这些iPSC衍生的成熟 细胞将成为研究与FBD相关的特定分子和时间方面的优秀候选者， FDD疾病表型。此外，它们将在神经退行性疾病领域产生更广泛的影响。 疾病，超越这些罕见疾病扩展到AD领域，为更好地治疗疾病提供了宝贵的选择。 了解调节APP加工，A？稳态和tau蛋白过程的机制 过度磷酸化，作为高通量药物筛选平台的替代范例，和 协助识别连接CAA相关血脑屏障的串扰途径 功能障碍和微血管的发展与神经血管单位和认知功能的变化 损伤 这项建议代表了纽约大学医学院研究人员的共同努力 和加州大学欧文分校，并建立在互补的专业知识，参与 研究人员和他们对脑淀粉样蛋白疾病的分子发病机制的长期兴趣。