Targeting the miR-155 signaling pathway to induce beneficial disease associated microglia subtypes in Alzheimer's Disease

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ABSTRACT Alzheimer’s Disease (AD) is currently the most prevalent neurodegenerative disorder in the world, with the number of cases expected to triple by 2050. Multiple pathological studies and data from genome wide association studies (GWAS) have identified microglia and genes specific to microglia as prominent mediators of AD pathogenesis and progression. Several laboratories have identified a genetic signature of microglia associated with AD and other neurodegenerative disorders, which have been dubbed “Disease Associated Microglia” (DAM) or “Microglia Neurodegenerative” (MGnD). It is still unknown whether these DAM/MGnD are beneficial or detrimental to AD pathology. One popular theory is that blocking DAM/MGnD formation may result in a beneficial effect in the context of AD, as this has been demonstrated in other animal models of neurodegeneration. To test this hypothesis in AD we selectively deleted microRNA 155, a microRNA demonstrated to be a major signaling component for the switch from homeostatic microglia to DAM/MGnD, in the microglia of mouse models of AD. Surprisingly, our data indicate that miR-155 deletion simultaneously enhanced expression of several canonical DAM/MGnD genes associated with phagocytosis, and dampened activity of pathways associated with inflammation and cytokine secretion. This surprising change resulted in an improvement of amyloid pathology and enhanced cognitive performance. To explain the mechanism for the acquisition of this signature, we assessed our transcriptomic data for molecular targets of miR-155 that have significance to AD onset in genetic studies and are upstream regulators of the genes we see differentially expressed or trending towards differential expression in our miR-155 ablation study data. Two miR-155 targets, SHIP1 and PU.1, have been identified by AD GWAS studies as top hits for AD onset and are transcriptional regulators of inflammation and phagocytosis, respectively. Taken together, these data led me to my hypothesis that the DAM/MGnD signatures are comprised of phagocytic and inflammatory “sub-features” which can be independently modulated by augmentation of SHIP1 and PU.1. I also hypothesize that the ablation of miR-155 will result in a similar transcriptional change in human microglia, given the identical conservation of miR-155 between mice and humans. In Aim 1 of this proposal, I propose to overexpress both SHIP1 and PU.1 in the microglia of AD mouse models using lentiviral vectors. This approach represents an extremely novel and translatable use of gene therapy technologies to address molecular mechanisms of microglial function. In Aim 2, I propose to recapitulate the gene signature observed in our microglia specific miR-155 ablation mouse experiments in human microglia like cells derived from induced pluripotent stem cells to tie the significance of these findings and this hypothesis to human health and disease.