Assessing the potential of reprogrammable microglia as a source of neurons in Alzheimer related dementias

评估可重编程小胶质细胞作为阿尔茨海默相关痴呆症神经元来源的潜力

• 批准号: 10192998
• 负责人: JEAN M HEBERT
• 金额: $ 45.76万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192998
• 关键词: ASCL1 gene; Ablation; Action Potentials; Address; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloidosis; Area; Axon; Biological; Blood - brain barrier anatomy; Brain; Cells; Complex; Data; Degenerative Disorder; Electrophysiology (science); Environment; Exhibits; Fostering; Future; Genetic; Human; Impaired cognition; In Situ; Injections; Libraries; Microglia; Modeling; Mus; Nature; Neocortex; Nerve Degeneration; Neurons; Pathologic; Pattern; Pharmacology; Preventive treatment; Process; Property; Protocols documentation; Public Health; Residual state; Resort; Site; Somatic Cell; Source; Testing; Time; Transplantation; Virus; Work; aging population; base; brain cell; cell type; cognitive benefits; curative treatments; effective therapy; genetic variant; in vivo; molecular subtypes; mouse model; neocortical; neural network; neuron loss; novel; precursor cell; progressive neurodegeneration; relating to nervous system; tau phosphorylation; transcription factor; transcriptome

ABSTRACT Alzheimer's disease and related dementias are a major public health problem because they currently affect between 5 and 6 million people in the U.S. alone and numbers are predicted to rise. There is no preventive or curative treatment at this time. Here, we propose studies aimed at developing microglia as a vehicle for introducing dispersed neurons into the neocortex as a potential future means of bolstering neuronal function in Alzheimer's disease and related dementias. The inherent plasticity of the adult neocortex, even under degenerative conditions, provides a suitable environment for the integration of transplant-derived neocortical neurons into existing circuits, as other groups have demonstrated. However, transplanted cortical precursor cells and their neuronal progeny do not significantly disperse from the transplant site. Therefore, given the wide areas of degeneration, a key challenge to this approach is the dispersion of the newly introduced cells without having to resort to highly invasive, densely arrayed cell injections. When experimentally depleted, microglia can repopulate the mouse neocortex within days. Based on our preliminary data, we hypothesize that this ability can be used to overcome the dispersion problem. We propose to transplant modified microglia that can outcompete endogenous residual microglia for repopulation. Once dispersed in the neocortex, these cells can be reprogrammed to become cortical neurons. Accordingly, we will test 1) if mouse and human microglia can be reprogrammed specifically to become cortical neurons; 2) if transplanted mouse and human microglia can disperse in the adult neocortex of normal mice and a murine model of Alzheimer's (5XfAD); and 3) if once dispersed in the parenchyma, microglia can be converted to neocortical neurons that become synaptically integrated. Successful completion of these aims will provide proof of concept that microglia can serve as a vehicle for introducing dispersed new neurons in neocortices exhibiting at least some of the complex features of Alzheimer's and related dementias. This will provide the impetus for further testing this approach in additional models, as well as assessing the cognitive benefits.

抽象的 阿尔茨海默氏病和相关痴呆症是一个主要的公共卫生问题，因为它们 目前仅在美国就有 5 至 600 万人受到影响，预计人数还会增加。有 目前没有预防性或治疗性治疗。在这里，我们提出旨在开发小胶质细胞的研究 将分散的神经元引入新皮质的载体，作为未来潜在的增强手段 阿尔茨海默病和相关痴呆症中的神经元功能。成人与生俱来的可塑性 新皮质，即使在退化的条件下，也为整合提供了合适的环境 正如其他研究小组所证明的那样，将新皮质神经元移植到现有的回路中。然而， 移植的皮质前体细胞及其神经元后代并没有显着地从 移植部位。因此，鉴于退化区域广泛，这种方法的一个关键挑战是 新引入的细胞的分散，无需采用高度侵入性、密集排列的细胞 注射。 当实验耗尽时，小胶质细胞可以在几天内重新填充小鼠新皮质。基于 根据我们的初步数据，我们假设这种能力可以用来克服色散问题。 我们建议移植修饰的小胶质细胞，使其能够在竞争中击败内源性残留小胶质细胞。 人口重新增加。一旦分散在新皮质中，这些细胞就可以重新编程成为皮质细胞 神经元。因此，我们将测试 1) 是否可以对小鼠和人类小胶质细胞进行专门重新编程 成为皮质神经元； 2）移植的小鼠和人类小胶质细胞是否可以分散在成年新皮质中 正常小鼠和阿尔茨海默病小鼠模型 (5XfAD)； 3）如果一旦分散在薄壁组织中， 小胶质细胞可以转化为突触整合的新皮质神经元。成功的 这些目标的完成将为小胶质细胞可以作为引入 新皮质中分散的新神经元至少表现出阿尔茨海默病的一些复杂特征 相关痴呆症。这将为在其他模型中进一步测试这种方法提供动力，因为 以及评估认知益处。