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

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.