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

摘要 阿尔茨海默氏症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500万至600万人受到影响，预计人数还会上升。有 目前尚无预防性或治愈性治疗。在这里，我们提出了旨在发展小胶质细胞的研究， 一种将分散的神经元引入新皮层的工具，作为一种潜在的未来手段， 阿尔茨海默病和相关痴呆症中的神经元功能。成年人固有的可塑性 新皮层，即使在退化的条件下，也为整合提供了合适的环境。 移植衍生的新皮层神经元到现有的电路中，正如其他小组所证明的那样。然而，在这方面， 移植的皮质前体细胞和它们的神经元后代并不显著地从皮质中分散。 移植部位因此，考虑到变性的广泛区域，这种方法的关键挑战是 分散新引入的细胞，而不必求助于高度侵入性的，密集排列的细胞， 注射剂 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层。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，可以胜过内源性残留的小胶质细胞， 再繁殖一旦分散在新皮层，这些细胞可以重新编程， 神经元因此，我们将测试1）小鼠和人类小胶质细胞是否可以被专门重新编程， 2）如果移植的小鼠和人类小胶质细胞可以分散在成年人的新皮层中 正常小鼠和阿尔茨海默氏病小鼠模型（5XfAD）的组织;和3）如果一旦分散在实质中， 小胶质细胞可以转化为突触整合的新皮层神经元。成功 这些目标的完成将提供小胶质细胞可以作为引入 新皮层中分散的新神经元至少表现出阿尔茨海默氏症的一些复杂特征， 相关的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， 以及评估认知益处。

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.