Selective targeting of Microglial APOE4 as a novel strategy to prevent TBI-induced neuroinflammatory dysfunction

ABSTRACT Epidemiologically, the apolipoprotein E4 (ApoE4) polymorphism has been consistently linked as the strongest genetic risk factor for late onset Alzheimer’s disease (LOAD). In comparison to the other APOE alleles, E4 homozygosity has been associated with a host of detrimental effects, including, but not limited to, dysfunctional neuroinflammation, metabolic deficits, and increased neuropathology. Coincidentally, the E4 allele has also been demonstrated to drive poorer outcome measures following traumatic brain injury (TBI), in humans and animal models. This begs an important question regarding the genetic impact of ApoE4 upon the cellular susceptibility and progression of pathophysiological responses following TBI. Consistent findings in rodent models expressing humanized APOE4 demonstrate altered neuroinflammation and microglial reactivity, compared to non-carriers, pointing toward a convergent cellular target. Our overarching goal for this proposal is to mechanistically examine how the genetic composition of APOE4 drives maladaptive neuroinflammatory sequelae following TBI, which is in turn linked with exacerbated functional outcomes. To do so, we will utilize a highly novel and emerging strategy to selectively target APOE4 alleles in microglia for either removal or allelic switching using two novel animal models. Our preliminary data demonstrate that either depletion of APOE4 from only microglia or switchin APOE4 to the neuroprotective APOE2 allele being linked with significant reductions in microglial reactivity TBI. This is critical as we additionally demonstrate that APOE4 alone is sufficient to drive chronic microglial heterogeneity towards the interferon-responsive state, which has been consistently linked with synaptic- and neuronal dysfunction. Therefore, using a vertically integrated and complementary approach we will decipher for the first time whether selectively targeting microglial APOE4 for removal or conversion into the protective APOE2 allele is sufficient to drive altered trajectories of neuroinflammation that are subsequently linked with improving both functional outcomes as well as neuropathological susceptibility and pathoprogession.